Lipid-rich plaque inhibitors

ABSTRACT

The present invention provides a lipid-rich plaque regressing agent comprising a compound represented by Formula: 
                 
 
in which ring A is a cyclic hydrocarbon or the like; ring B is a heterocyclic ring or the like; each of X and Y is —NR 1 — (in which R 1  is a hydrocarbon or the like); D is a C 1-3  alkylene group or the like; E is —NH— or the like; G is a bond or the like; and Ar is an aryl or the like; D may be taken together with a constituent atom of the ring B to form a ring, and R 4  may be taken together with a constituent atom of the ring B to form a ring.

This application is the National Phase filing of International PatentApplication No. PCT/JP01/06070, filed 13 Jul. 2001.

TECHNICAL FIELD

The present invention relates to a lipid-rich plaque regressing agentuseful in preventing or treating acute coronary artery syndrome such asacute myocardial infarction, unstable angina and the like, peripheralartery occlusion and the like.

BACKGROUND ART

As an agent for reducing the level of blood cholesterol which causesarteriosclerosis, an agent which inhibits the absorption of bile acid bycapturing it such as cholestyramine and cholestipol (U.S. Pat. No.4,027,009), an agent which inhibits the absorption of cholesterol via anintestinal tract by inhibiting an acyl coenzyme A cholesterol acyltransferase (ACAT) such as melinamide (French Patent 1476569) and acholesterol synthesis inhibitor, especially an agent which inhibits3-hydroxy-3-methylgultaryl coenzyme A (HMG-CoA) reductase such aslovastatin (U.S. Pat. No. 4,231,938), simvastatin (U.S. Pat. No.4,444,784) and pravastatin (U.S. Pat. No. 4,346,227) are employed inpharmaceuticals.

However, an HMG-CoA reductase inhibitor may cause a problem associatedwith side effects due to its inhibitory effect not only on cholesterolbiosynthesis but also on a biologically essential component such asubiquinone, dolichol and hem A.

Acute coronary artery syndrome (for example, unstable angina, acutemyocardial infarction and ischemic sudden death) is caused by thedestruction of a coronary artery plaque (atheroma) followed by theformation of a thrombus and the resultant plugging of the lumen of thecoronary artery. Peripheral artery occlusion is caused by thedestruction of an artery plaque (atheroma) followed by the formation ofa thrombus and the resultant plugging of the lumen of a peripheralartery. These diseases are related closely with the characteristics ofthe plaque, and a lipid-rich plaque formed by the deposition of amacrophage retaining lipids such as cholesterol extensively onto aninner wall of a blood vessel is believed to cause acute coronary arterysyndrome and peripheral artery occlusion.

Accordingly, the regression and removal of a lipid-rich plaque are veryimportant for preventing or treating acute coronary artery syndrome suchas acute myocardial infarction and unstable angina as well as peripheralartery occlusion. Also since a lipid-rich plaque is observed in a humanwhose blood cholesterol level is not high and a lipid-rich plaque onceformed is difficult to be removed, an agent capable of regressing such alipid-rich plaque efficiently has been desired. Since a lipid-richplaque is observed in a human whose blood cholesterol level is not high,the ACAT inhibition to reduce the intestinal absorption of cholesterolis not considered to be sufficient for regressing and removing thelipid-rich plaque.

SUMMARY OF THE INVENTION

The present invention provides a lipid-rich plaque regressing agentuseful in preventing or treating acute coronary artery syndrome such asacute myocardial infarction and unstable angina as well as peripheralartery occlusion. The present invention also provides a lipid-richplaque regressing agent which is migrated readily into a blood vessel ortissue to act directly on a macrophage in which lipids such ascholesterol are retained extensively whereby exerting a directregressing effect on an arteriosclerotic focus.

In consideration of the above, we studied intensively and, as a result,we found out that an ACAT inhibitor having a certain structure has anunexpectedly high lipid-rich plaque regressing effect, which issufficiently effective even at a concentration which does not affect theblood cholesterol level, and thereby completed the present invention.

Thus, the present invention relates to:

-   (1) a lipid-rich plaque regressing agent comprising a compound    represented by Formula [I]:    in which ring A is an optionally substituted cyclic hydrocarbon or    an optionally substituted heterocyclic ring; ring B is a 5- or    6-membered homocyclic or heterocyclic ring; each of X and Y is —NR¹—    (in which R¹ is a hydrogen atom, optionally substituted hydrocarbon    group, optionally substituted hydroxyl group or optionally    substituted amino group), —O—, —S—, —CO—, —CS—, —C(R²)R^(2a)— (in    which each of R² and R^(2a) is a hydrogen atom, optionally    substituted hydroxyl group or optionally substituted hydrocarbon    group), —N═ or ═CR³— (in which R³ is a hydrogen atom, halogen atom,    optionally substituted hydrocarbon group, optionally substituted    hydroxyl group or a mercapto group which may be substituted by an    optionally substituted hydrocarbon group); D is a C₁₋₃ alkylene    group which may be substituted by an oxo group or thioxo group, —NH—    or —CH₂NH—; E is —NR⁴— (in which R⁴ is a hydrogen atom or optionally    substituted hydrocarbon group), —O—, —S(O)n- (n is 0, 1 or 2) or    —CONR⁵— (in which R⁵ is a hydrogen atom or optionally substituted    hydrocarbon group); G is a bond or C₁₋₃ alkylene group; Ar is an    optionally substituted aryl group or optionally substituted    heterocyclic group, D may be taken together with a constituent atom    in the ring B to form a 5- to 7-membered ring which may be    substituted by an oxo group or thioxo group, R⁴ may be taken    together with a constituent atom of the ring B to form a 5- to    7-membered ring which may be substituted by an oxo group or thioxo    group, and the ring B may have a further substituent in addition to    -D-E-G-Ar or a salt thereof;-   (2) the lipid-rich plaque regressing agent according to the    above-mentioned (1) comprising a compound represented by Formula    [II]:    in which ring A′ is an optionally substituted 6-membered cyclic    hydrocarbon group; ring C is an optionally substituted benzene ring;    one of X′ and Z is —NR^(1′)— (in which R^(1′) is a hydrogen atom,    optionally substituted hydrocarbon group or optionally substituted    amino group), —O— or —S— and the other is —CO—, —CS— or    —C(R^(2′))R^(2a′)— (in which each of R^(2′) and R^(2a′) is a    hydrogen atom or optionally substituted hydrocarbon group), or one    of them is —N═ and the other is ═CR^(3′)— (in which R^(3′) is a    hydrogen atom, halogen atom, optionally substituted hydrocarbon    group, optionally substituted amino group, optionally substituted    hydroxyl group or mercapto group which may be substituted by an    optionally substituted hydrocarbon group);    is a single bond or double bond; Y′, when    adjacent to Y′ is a single bond, is    in which R⁶ is a hydrogen atom, hydroxyl group or optionally    substituted hydrocarbon group) or a nitrogen atom, Y′, when    adjacent to Y′ is a double bond, is a carbon atom; D′ is a C₁₋₃    alkylene group which may be substituted by an oxo group or thioxo    group; E′ is —NR⁷— (in which R⁷ is a hydrogen atom or optionally    substituted hydrocarbon group), —O— or —S(O)n- (in which n is 0, 1    or 2); G′ is a bond or C₁₋₃ alkylene group; Ar′ is an optionally    substituted aryl group or optionally substituted heterocyclic group,    D′ may be taken together with Z to form a 5- to 7-membered ring    which may be substituted by an oxo group or thioxo group, R⁷ may be    taken together with Z to form a 5- to 7-membered ring which may be    substituted by an oxo group or thioxo group or a salt thereof;-   (3) the lipid-rich plaque regressing agent according to the    above-mentioned (1) comprising a compound represented by Formula    [III]:    in which each of ring A″, ring C′ and ring D is an optionally    substituted benzene ring, X″ is —NR⁸— (in which R⁸ is a hydrogen    atom or optionally substituted hydrocarbon group), —O— or —S—, U is    —(CH₂)m-(in which m is 1 or 2) or —NH—, R^(a) is a hydrogen atom or    optionally substituted hydrocarbon group) or a salt thereof;-   (4) the lipid-rich plaque regressing agent according to the    above-mentioned (1) comprising a compound represented by Formula    [IV]:    in which ring A″′ is an optionally substituted benzene ring, Q is an    optionally substituted aromatic ring, W is —CH₂—, —CO— or —CS—, V is    or W and V are taken together to form    Y″ is —CH₂—, —O—, —S—, —CO—, —CS— or —NR⁹— (in which R⁹ is a    hydrogen atom or hydrocarbon group), U′ is —NH—, —CH₂— or —CH₂NH—,    R^(b) is a hydrogen atom or optionally substituted hydrocarbon    group,    is a single bond or double bond or a salt thereof;-   (5) the lipid-rich plaque regressing agent according to the    above-mentioned (1) comprising a compound represented by Formula    [V]:    in which each of R¹⁰ and R¹¹ is a hydrogen atom, halogen atom,    optionally substituted linear hydrocarbon group or hydroxyl group    which may be substituted by an optionally substituted linear    hydrocarbon group, or the both may be taken together with the    adjacent carbon atoms to form an optionally substituted cyclic    hydrocarbon or a dihydrofuran ring which may be substituted by an    oxo group, ring I is an optionally substituted benzene ring or    optionally substituted pyridine ring (preferably optinally    substituted with benzen ring), ring J is an optionally substituted    benzene ring or optionally substituted pyridine ring or a salt    thereof;-   (6) the lipid-rich plaque regressing agent according to the    above-mentioned (5) wherein each of R¹⁰ and R¹¹ is a hydrogen atom,    halogen atom or optionally substituted linear hydrocarbon group, or    the both may be taken together with the adjacent carbon atoms to    form an optionally substituted cyclic hydrocarbon;-   (7) the lipid-rich plaque regressing agent according to the    above-mentioned (1) comprising a compound represented by Formula    [VI]:    in which each of R¹² and R¹³ is a hydrogen atom, halogen atom or    optionally substituted linear hydrocarbon group, or the both may be    taken together with the adjacent carbon atoms to form an optionally    substituted cyclic hydrocarbon,    is an optionally substituted phenyl group, ring L is an optionally    substituted benzene ring or optionally substituted pyridine ring or    a salt thereof;-   (8) the lipid-rich plaque regressing agent according to the    above-mentioned (1) which is a prophylactic and therapeutic agent    against acute coronary artery syndrome;-   (9) the lipid-rich plaque regressing agent according to the    above-mentioned (1) which is a prophylactic and therapeutic agent    against acute myocardial infarction;-   (10) the lipid-rich plaque regressing agent according to the    above-mentioned (1) which is a prophylactic and therapeutic agent    against unstable angina;-   (11) the lipid-rich plaque regressing agent according to the    above-mentioned (1) which is a prophylactic and therapeutic agent    against peripheral artery occlusion;-   (12) a compound represented by Formula [V]:    in which each of R¹⁰ and R¹¹ is a hydrogen atom, halogen atom,    optionally substituted linear hydrocarbon group or hydroxyl group    which may be substituted by an optionally substituted linear    hydrocarbon group, or the both may be taken together with the    adjacent carbon atoms to form an optionally substituted cyclic    hydrocarbon or a dihydrofuran ring which may be substituted by an    oxo group, ring I is an optionally substituted benzene ring or    optionally substituted pyridine ring (preferably optionally    substituted benzene ring), ring J is an optionally substituted    benzene ring or optionally substituted pyridine ring, provided that    when R¹⁰ is a hydrogen atom then R¹¹ is a substituted linear    hydrocarbon group, or a salt thereof;-   (13) the compound according to the above-mentioned (12) wherein each    of R¹⁰ and R¹¹ is a hydrogen atom, halogen atom or optionally    substituted linear hydrocarbon group, or the both are taken together    with the adjacent carbon atoms to form an optionally substituted    cyclic hydrocarbon;-   (14) the compound according to the above-mentioned (12) wherein each    of R¹⁰ and R¹¹ is a halogen atom or optionally substituted C₁₋₇    alkyl group;-   (15) the compound according to the above-mentioned (12) wherein the    cyclic hydrocarbon is a C₅₋₇ cyclic hydrocarbon;-   (16) the compound according to the above-mentioned (12) wherein the    ring J is a benzene ring substituted by halogenated alkyl group    and/or halogen atom;-   (17) the compound according to the above-mentioned (12) wherein the    ring I is a benzene ring which may be substituted by alkyl group,    halogenated alkyl group or halogen atom;-   (18) a compound represented by Formula [VI]:    in which each of R¹² and R¹³ is a hydrogen atom, halogen atom or    optionally substituted linear hydrocarbon group, or the both may be    taken together with the adjacent carbon atoms to form an optionally    substituted cyclic hydrocarbon,    is an optionally substituted phenyl group (provided that    2-chlorophenyl and 2-fluorophenyl are excluded), ring L is an    optionally substituted benzene ring or optionally substituted    pyridine ring, provided that when    is a phenyl group, then R¹³ is not a methyl group, and when    is a 2-methylphenyl group, then R¹³ is not a chlorine atom, or a    salt thereof;-   (19) the compound according to the above-mentioned (18) wherein each    of R¹² and R¹³ is a halogen atom or C₁₋₃ alkyl group;-   (20) the compound according to the above-mentioned (18) wherein the    cyclic hydrocarbon is a C₅₋₇ cyclic hydrocarbon;-   (21) the compound according to the above-mentioned (18) wherein:    is a phenyl group which may be substituted by a C₁₋₃ alkyl group;-   (22) the compound according to the above-mentioned (18) wherein the    ring L is a substituted benzene ring;-   (23)    2-[7-Chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-4-(3-chloro-4-fluorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-4-(3-chloro-4-fluorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-6-methyl-4-(3-methylphenyl)-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-6-methyl-4-(3-methylphenyl)-2-oxo-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-2-oxo-4-phenyl-6-[(4-phenylpiperazin-1-yl)methyl]-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-2-oxo-4-phenyl-6-[(4-phenylpiperazin-1-yl)methyl]-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-6-[[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl]methyl]-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-6-[[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl]methyl]-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-6-[[4-(3-methylphenyl)piperidin-1-yl]methyl]-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-6-[[4-(3-methylphenyl)piperidin-1-yl]methyl]-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;    or a salt thereof;-   (24) a prodrug of the compound according to any one of the    above-mentioned (12), (18) and (23);-   (25) a pharmaceutical composition comprising the compound according    to any one of the above-mentioned (12), (18) and (23) or a prodrug    thereof;-   (26) an agent for inhibiting progression of an arteriosclerotic    focus comprising a compound having a lipid-rich plaque regressing    effect or a salt thereof;-   (27) the agent according to the above-mentioned (26) in combination    with an HMG-CoA reductase inhibitor.-   (28) a method for producing the compound according to the    above-mentioned (12) or a salt thereof, which comprises reacting a    compound represented by Formula [VII]:    [in which each symbol is as defined in the above-mentioned (12)] or    a salt thereof or a reactive derivative thereof with a compound    represented by Formula [VIII]:    [in which each symbol is as defined in the above-mentioned (12)] or    a salt thereof;-   (29) a method for producing the compound according to the    above-mentioned (18) or a salt thereof, which comprises reacting a    compound represented by Formula [IX]:    [in which each symbol is as defined in the above-mentioned (18)] or    a salt thereof or a reactive derivative thereof with a compound    represented by Formula [X]:    [in which each symbol is as defined in the above-mentioned (18)] or    a salt thereof;-   (30) a method for producing the compound according to the    above-mentioned (18) or a salt thereof, which comprises reacting a    compound represented by Formula [XI]:    [in which each symbol is as defined in the above-mentioned (18)] or    a salt thereof with a compound represented by Formula [XII]:    [in which each symbol is as defined in the above-mentioned (18)] or    a salt thereof;-   (31) a method for regressing a lipid-rich plaque in a mammal, which    comprises administering an effective amount of the compound    according to the above-mentioned (1) or a salt thereof to a mammal;-   (32) a method for preventing and treating acute coronary artery    syndrome in a mammal, which comprises administering an effective    amount of a compound according to the above-mentioned (1) or a salt    thereof to a mammal;-   (33) a method for preventing and treating acute myocardial    infarction in a mammal, which comprises administering an effective    amount of the compound according to the above-mentioned (1) or a    salt thereof to a mammal;-   (34) a method for preventing and treating unstable angina in a    mammal, which comprises administering an effective amount of the    compound according to the above-mentioned (1) or a salt thereof to a    mammal;-   (35) a method for preventing and treating peripheral artery    occlusion in a mammal, which comprises administering an effective    amount of the compound according to the above-mentioned (1) or a    salt thereof to a mammal;-   (36) a method for regressing a lipid-rich plaque in a mammal, which    comprises administering an effective amount of the compound    according to the above-mentioned (12), a salt thereof or a prodrug    thereof to a mammal;-   (37) a method for regressing a lipid-rich plaque in a mammal, which    comprises administering an effective amount of the compound    according to the above-mentioned (18), a salt thereof or a prodrug    thereof to a mammal;-   (38) a use of the compound according to the above-mentioned (1) or a    salt thereof for producing a lipid-rich plaque regressing agent;-   (39) a use of the compound according to the above-mentioned (1) or a    salt thereof for producing a prophylactic and therapeutic agent    against acute coronary artery syndrome;-   (40) a use of the compound according to the above-mentioned (1) or a    salt thereof for producing a prophylactic and therapeutic agent    against acute myocardial infarction;-   (41) a use of the compound according to the above-mentioned (1) or a    salt thereof for producing a prophylactic and therapeutic agent    against unstable angina;-   (42) a use of the compound according to the above-mentioned (1) or a    salt thereof for producing a prophylactic and therapeutic agent    against peripheral artery occlusion;-   (43) a use of the compound according to the above-mentioned (12), a    salt thereof or a prodrug thereof for producing a lipid-rich plaque    regressing agent;-   (44) a use of the compound according to the above-mentioned (18), a    salt thereof or a prodrug thereof for producing a lipid-rich plaque    regressing agent, and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

In Formula [I] shown above, a cyclic hydrocarbon in an optionallysubstituted cyclic hydrocarbon represented by ring A may, for example,be a C₃₋₁₀ saturated hydrocarbon ring (e.g., cyclopropane ring,cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ringand the like); C₅₋₈ unsaturated hydrocarbon ring (e.g., cyclopentenering, cyclohexene ring, cycloheptene ring, benzene ring and the like).Among those listed above, a C₅₋₇ saturated hydrocarbon ring (e.g.,cyclopentane ring, cyclohexane ring and the like), C₅₋₆ unsaturatedhydrocarbon ring (e.g., cyclopentene ring, cyclohexene ring, benzenering and the like) are preferred, with a benzene ring being especiallypreferred.

A substituent in an optionally substituted cyclic hydrocarbon describedabove may for example be:

-   (i) an optionally halogenated C₁₋₄ alkyl group (for example, methyl,    chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,    ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl, isopropyl,    3,3,3-trifluoropropyl, butyl and the like);-   (ii) a C₁₋₄ alkyl group substituted by an amino group (for example,    aminomethyl, 2-aminoethyl and the like);-   (iii) a C₁₋₄ alkyl group substituted by a mono- or di-C₁₋₄    alkylamino group (for example, methylaminomethyl,    dimethylaminomethyl, 2-methylaminoethyl, 2-dimethylaminoethyl and    the like);-   (iv) a C₁₋₄ alkyl group substituted by a carboxyl group (for    example, carboxymethyl, carboxyethyl and the like);-   (v) a C₁₋₄ alkyl group substituted by a C₁₋₄ alkoxy-carbonyl group    (for example, methoxycarbonylethyl, ethoxycarbonylethyl and the    like);-   (vi) a C₁₋₄ alkyl group substituted by a hydroxyl group (for    example, hydroxymethyl, hydroxyethyl and the like);-   (vii) a C₁₋₄ alkyl group substituted by a C₁₋₄ alkoxy group which    may be substituted by a C₁₋₄ alkoxy group or phenoxy group (for    example, methoxymethyl, methoxyethyl, ethoxyethyl and the like);-   (viii) a C₃₋₆ cycloalkyl group (for example, cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl and the like);-   (ix) a halogen atom (for example, fluorine, chlorine, bromine,    iodine and the like);-   (x) a nitro group;-   (xi) a cyano group;-   (xii) a hydroxyl group;-   (xiii) a C₁₋₄ alkoxy group which may be substituted by an optionally    halogenated C₁₋₄ alkoxy group (for example, methoxy,    difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,    propyloxy, butoxy, isopropyloxy and the like), C₁₋₄ alkoxy group or    phenoxy group;-   (xiv) a C₁₋₄ alkylthio group which may be substituted by an    optionally halogenated C₁₋₄ alkylthio group (for example,    methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,    propylthio, isopropylthio, butylthio and the like), C₁₋₄ alkoxy    group or phenoxy group;-   (xv) an amino group:-   (xvi) a mono- or di-C₁₋₄ alkylamino group (for example, methylamino,    ethylamino, propylamino, dimethylamino, diethylamino and the like);-   (xvii) a cyclic amino group (for example, a 5- to 9-membered cyclic    amino group which may contain 1 to 3 heteroatoms such as oxygen and    sulfur atoms in addition to nitrogen atoms, specifically,    pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and the like);-   (xviii) a C₁₋₄ alkyl-carbonylamino group (for example, acetylamino,    propionylamino, butyrylamino and the like);-   (xix) an aminocarbonyloxy group;-   (xx) a mono- or di-C₁₋₄ alkylamino-carbonyloxy group (for example,    methylaminocarbonyloxy, ethylaminocarbonyloxy,    dimethylaminocarbonyloxy, diethylaminocarbonyloxy and the like);-   (xxi) a C₁₋₄ alkylsulfonylamino group (for example,    methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino and the    like);-   (xxii) a C₁₋₄ alkoxy-carbonyl group (for example, methoxycarbonyl,    ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl and the like);-   (xxiii) a benzyloxycarbonyl group;-   (xxiv) a carboxyl group;-   (xxv) a C₁₋₆ alkyl-carbonyl group (for example, methylcarbonyl,    ethylcarbonyl, butylcarbonyl and the like);-   (xxvi) a C₃₋₆ cycloalkyl-carbonyl (for example, cyclohexylcarbonyl    and the like);-   (xxvii) a carbamoyl group;-   (xxviii) a mono- or di-C₁₋₄ alkylcarbamoyl group (for example,    methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl,    diethylcarbamoyl, dibutylcarbamoyl and the like),-   (xxix) a C₁₋₆ alkylsulfonyl group (for example, methylsulfonyl,    ethylsulfonyl, propylsulfonyl and the like);-   (xxx) a C₁₋₆ alkyl group substituted by [1] C₁₋₄ alkyl (e.g.,    methyl), [2] C₁₋₄ alkylsulfonyl (e.g., methylsulfonyl), [3], a C₆₋₁₂    aryl group which may have optionally halogenated C₁₋₄ alkyl (e.g.,    methyl, trifluoromethyl), halogen (e.g., fluorine, chlorine) or a    hydroxyl group (for example, phenyl, naphthyl, hydroxyphenyl,    methylphenyl, chlorophenyl and the like), [4] C₇₋₁₅ aralkyl (for    example, benzyl), [5] C₁₋₄ alkoxy-C₁₋₄ alkyl (for example,    propoxyethyl and the like), [6] a 5- to 9-membered heterocyclic    group which contains 1 to 3 heteroatoms such as nitrogen, oxygen and    sulfur atoms in addition to carbon atoms (for example, piperidinyl,    piperazinyl, morpholinyl, thienyl, furyl, pyridyl, pyrimidinyl,    thiazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl,    benzoisoxazolyl and the like), [7] a cyclic amino group substituted    by one or two substituents selected from hydroxyl, thiol, oxo,    thioxo and the like (for example, a 5- to 9-membered cyclic amino    group which may contain 1 to 3 heteroatoms such as oxygen and sulfur    atoms in addition to nitrogen atoms, specifically, pyrrolidinyl,    piperidinyl, piperazinyl, 3,6-dihydropyridin-1(2H)-yl,    [1,3]thiazolo[4,5-b]pyridin-3(2H)-yl, morpholinyl), (for example,    morpholinomethyl, 4-phenyl-1-piperazinylmethyl, 2-morpholinoethyl,    3-piperazinylpropyl, 4-methylsulfonyl-piperazinylmethyl,    4-benzyl-1-piperazinylmethyl,    4-(4-hydroxyphenyl)-1-piperazinylmethyl, 4-hydroxypiperidinylmethyl,    4-hydroxy-4-phenylpiperidinylmethyl, 4-phenylpiperidinylmethyl,    4-(2-pyridyl)-1-piperazinylmethyl,    4-(4-hydroxyphenyl)-1-piperazinylmethyl,    (4-phenyl-3,6-dihydropyridin-1(2H)-yl)methyl and the like);-   (xxxi) a C₁₋₄ alkyl group substituted by a C₁₋₆ alkyl-carbonyloxy    group (for example, methylcarbonyloxy, ethylcarbonyloxy,    butylcarbonyloxy and the like);-   (xxxii) a C₁₋₄ alkyl group substituted by an amino group substituted    by a 5- to 9-membered heterocyclic group which contains 1 to 3    heteroatoms such as nitrogen, oxygen and sulfur atoms in addition to    carbon atoms (for example, thienyl, furyl, pyridyl, pyrimidinyl,    thiazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl,    benzoisoxazolyl and the like) (e.g., methyl(2-pyridyl)amino);-   (xxxiii) a C₁₋₄ alkyl group substituted by an amino group    substituted by C₁₋₄ alkyl and C₁₋₄ alkyl-carbonyl (e.g.,    methyl(methylcarbonyl)amino);-   (xxxiv) a C₁₋₄ alkyl group substituted by an amino group substituted    by C₁₋₄ alkyl and C₆₋₁₂ aryl-carbonyl (e.g., methyl(benzoyl)amino);-   (xxxv) a C₁₋₄ alkyl group substituted by a C₁₋₆ alkyl-carbonyloxy    group (for example, methylcarbonyloxy, ethylcarbonyloxy,    butylcarbonyloxy and the like);-   (xxxvi) a C₁₋₄ alkyl group substituted by a mono- or di-C₁₋₄    alkoxy-C₁₋₄-alkyl-amino group (e.g., butoxypropylamino);-   (xxxvii) a C₁₋₄ alkyl group substituted by a 5- to 9-membered    heterocyclic group which contains 1 to 3 heteroatoms such as    nitrogen, oxygen and sulfur atoms in addition to carbon atoms (for    example, thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl,    benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl and    the like)-thio group (e.g., 2-pyridylthio);-   (xxxviii) an oxo group;-   (xxxix) a C₁₋₄ alkoxy-carbonyl C₂₋₆alkenyl group (e.g.,    methoxycarbonylvinyl and the like);-   (xxxx) a C₂₋₆ alkenyl group substituted by a carboxyl group (e.g.,    carboxyvinyl and the like);-   (xxxxi) a C₁₋₄ alkyl group substituted by a cyano group (e.g.,    cyanomethyl), and “an optionally substituted heterocyclic group”    described below itself may also be employed as a substituent on said    cyclic hydrocarbon. The same or difference 1 to 5, preferably 1 to 3    of these substituents may be in any substitutable positions.

Among those listed above, preferred substituents are (i) a halogen atom(for example, fluorine, chlorine, bromine and the like), (ii) anoptionally halogenated C₁₋₄ alkyl group (for example, methyl,chloromethyl, difluoromethyl, trifluoromethyl, ethyl, propyl, isopropyland the like), (iii) a C₃₋₆ cycloalkyl group (for example, cyclopropyl,cyclobutyl and the like), (iv) a hydroxyl group, (v) an optionallyhalogenated C₁₋₄ alkoxyl group (for example, methoxy, difluoromethoxy,trifluoromethoxy, ethoxy and the like), (vi) an optionally halogenatedC₁₋₄ alkylthio group (for example, methylthio, trifluorothio, ethylthioand the like), (vii) an amino group, (viii) a mono- or di-C₁₋₄alkylamino group (for example, methylamino, ethylamino, dimethylamino,diethylamino and the like), (ix) a C₁₋₄ alkoxy-carbonyl group (forexample, methoxycarbonyl, ethoxycarbonyl and the like), (x) a C₁₋₆ alkylgroup substituted by a cyclic amino group (for example, a 5- to9-membered cyclic amino group which may contain 1 to 3 heteroatoms suchas oxygen and sulfur atoms in addition to nitrogen atoms, specifically,pyrrolidinyl, piperidinyl, morpholinyl and the like) which may besubstituted by a C₆₋₁₂ aryl group (for example, phenyl, naphthyl and thelike), (for example, morpholinomethyl, 4-phenyl-1-piperazinylmethyl,2-morpholinoethyl, 3-piperazinylpropyl and the like) and (xi) a carboxylgroup and the like, with (i) a halogen atom (for example, fluoro, chloroand the like), (ii) a C₁₋₄ alkyl (for example, methyl, ethyl and thelike), (iii) a C₃₋₆ cycloalkyl group (for example, cyclopropyl,cyclobutyl and the like), (iv) a hydroxyl group, (v) a C₁₋₄ alkoxy group(for example, methoxy, ethoxy and the like), (vi) a C₁₋₆ alkyl groupsubstituted by a cyclic amino group (for example, a 5- to 9-memberedcyclic amino group which may contain 1 to 3 heteroatoms such as oxygenand sulfur atoms in addition to nitrogen atoms, specifically,pyrrolidinyl, piperidinyl, piperazinyl, 3,6-dihydropyridin-1(2H)-yl,morpholinyl and the like) which may be substituted by a C₆₋₁₂ aryl group(for example, phenyl, naphthyl and the like), (for example,morpholinomethyl, 4-phenyl-1-piperazinylmethyl, 2-morpholinoethyl,(4-phenyl-3,6-dihydropyridin-1(2H)-ylmethyl), 3-piperazinylpropyl andthe like) and (vii) a carboxyl group being especially preferred.

In Formula [I] shown above, a heterocyclic ring in an optionallysubstituted heterocyclic group represented by ring A may, for example,be a 5- to 9-membered, preferably 5- or 6-membered aromatic heterocyclicring having 1 to 4, preferably 1 to 2 heteroatoms such as nitrogen,oxygen and sulfur atoms in addition to carbon atoms.

Such an aromatic heterocyclic group may, for example, be an aromaticmonocyclic heterocyclic ring such as furan ring, thiophene ring, pyrrolering, oxazoline ring, isoxazoline ring, thiazoline ring, isothiazolinering, imidazole ring, pyrazole ring, 1,2,3-oxadiazole ring,1,2,4-oxadiazole ring, 1,3,4-oxadiazole ring, 1,2,5-oxadiazole ring,1,2,3-thiadiazole ring, 1,2,4-thiadiazole ring, 1,3,4-thiadiazole ring,1,2,3-triazole ring, 1,2,4-triazole ring, tetrazole ring, pyridine ring,pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring and thelike. Among those listed above, furan ring, thiophene ring, pyrrolering, oxazole ring, isoxazole ring, imidazole ring, pyrazole ring,1,2,3-thiadiazole ring, 1,2,4-triazole ring, tetrazole ring, pyridinering, pyridazine ring, thiazole ring and thiadiazoline ring arepreferred, with furan ring, thiophene ring and pyridine ring beingespecially preferred.

A substituent which may be possessed by an optionally substitutedheterocyclic group described above may, for example, be (i) anoptionally halogenated C₁₋₄ alkyl group (for example, methyl,chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,2,2-dibromoethyl, 2,2,2-trifluoroethyl, propyl, isopropyl,3,3,3-trifluoropropyl, butyl and the like); (ii) a C₃₋₆ cycloalkyl group(for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and thelike); (iii) a halogen atom (for example, fluorine, chlorine, bromine,iodine and the like); (iv) a nitro group; (v) a cyano group; (vi) ahydroxyl group; (vii) an optionally halogenated C₁₋₄ alkoxy group (forexample, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy,ethoxy, 2,2,2-trifluoroethoxy, propyloxy, butyloxy, isopropyloxy and thelike); (viii) an optionally halogenated C₁₋₄ alkylthio group (forexample, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio and the like); (ix) an amino group;(x) a mono- or di-C₁₋₄ alkylamino group (for example, methylamino,ethylamino, propylamino, dimethylamino, diethylamino and the like); (xi)a cyclic amino group [for example, a 5- to 9-membered cyclic amino groupwhich may contain 1 to 3 heteroatoms such as oxygen and sulfur atoms inaddition to nitrogen atoms (for example, pyrrolidino, piperidino,morpholino and the like) and the like]; (xii) a C₁₋₄ alkyl-carbonylaminogroup (for example, acetylamino, propionylamino, butyrylamino and thelike); (xiii) an aminocarbonyloxy group; (xiv) a mono- or di-C₁₋₄alkylaminocarbonyloxy group (for example, methylaminocarbonyloxy,ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxyand the like); (xv) a C₁₋₄ alkylsulfonylamino group (for example,methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino and thelike); (xvi) a C₁₋₄ alkoxy-carbonyl group (for example, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl and the like); (xvii)a carboxyl group; (xviii) a C₁₋₆ alkyl-carbonyl group (for example,methylcarbonyl, ethylcarbonyl, butylcarbonyl and the like); (xix) a C₃₋₆cycloalkylcarbonyl group (for example, cyclohexylcarbonyl and the like),(xx) a carbamoyl group; (xxi) a mono- or di-C₁₋₄ alkylcarbamoyl group(for example, methylcarbamoyl, ehtylcarbamoyl, propylcarbamoyl,butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl and the like); (xxii)a C₁₋₆ alkylsulfonyl group (for example, methylsulfonyl, ethylsulfonyl,propylsulfonyl and the like); (xxiii) a C₃₋₆ cycloalkylsulfonyl (forexample, cyclopentylsulfonyl, cyclohexylsulfonyl and the like), (xxiv) aC₆₋₁₀ aryl group (for example, phenyl, naphthyl and the like); (xxv)phenoxy, benzoyl, phenoxycarbonyl, phenyl-C₁₋₄ alkylcarbamoyl,phenylcarbamoyl, phenyl-C₁₋₄ alkyl-carbonylamino, benzoylamino,phenyl-C₁₋₄ alkylsulfonyl, phenylsulfonyl, phenyl-C₁₋₄ alkylsulfinyl,phenyl-C₁₋₄ alkylsulfonylamino or phenylsulfonylamino group [each phenylgroup or naphtyl group may have in its any substitutable positions 1 to3 substituents such as C₁₋₄ alkyl group (for example, methyl, ethyl,propyl, butyl, isopropyl and the like), C₁₋₄ alkoxy group (for example,methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy and the like),halogen atom (for example, chloro, bromo, iodo and the like), hydroxylgroup, benzyloxy group, amino group, mono- or di-C₁₋₄ alkylamino group(for example, methylamino, dimethylamino, ethylamino, diethylamino,diisopropylamino and the like), nitro group, C₁₋₆ alkylcarbonyl group(for example, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl and the like) and thelike]. The same or different 1 to 5, preferably 1 to 3 of thesesubstituents may be in any substitutable positions.

Among those listed above, preferred substituents are (i) a halogen atom(for example, fluorine, chlorine, bromine and the like), (ii) anoptionally halogenated C₁₋₄ alkyl group (for example, methyl,chloromethyl, difluoromethyl, trifluoromethyl, ethyl, propyl, isopropyland the like), (iii) a C₃₋₆ cycloalkyl group (for example, cyclopropyl,cyclobutyl and the like), (iv) a hydroxyl group, (v) an optionallyhalogenated C₁₋₄ alkoxyl group (for example, methoxy, difluoromethoxy,trifluoromethoxy, ethoxy and the like), (vi) an optionally halogenatedC₁₋₄ alkylthio group (for example, methylthio, trifluoromethylthio,ethylthio and the like), (vii) an amino group, (viii) a mono- or di-C₁₋₄alkylamino group (for example, methylamino, ethylamino, dimethylamino,diethylamino and the like), (ix) a C₁₋₄ alkoxy-carbonyl group (forexample, methoxycarbonyl, ethoxycarbonyl and the like) and (x) acarboxyl group and the like, with (i) a halogen atom (for example,fluoro, chloro and the like), (ii) a C₁₋₄ alkyl (for example, methyl,ethyl and the like), (iii) a C₃₋₆ cycloalkyl group (for example,cyclopropyl, cyclobutyl and the like), (iv) a hydroxyl group, (v) a C₁₋₄alkoxy group (for example, methoxy, ethoxy and the like) and (vi) acarboxyl group being especially preferred.

In Formula [I] shown above, a 5- or 6-membered homocyclic ringrepresented by ring B may, for example, be a cyclopentane ring,cyclohexane ring, cyclopentene ring, cyclohexene ring, cyclopentadienering, cyclohexadiene ring, benzene ring and the like. Among those listedabove, a cyclohexane ring, cyclohexene ring, cyclopentadiene ring andbenzene ring are preferred, with a cyclohexane ring and cyclopentadienering being especially preferred.

In Formula [I] shown above, a 5- or 6-membered heterocyclic ringrepresented by ring B may, for example, be a 5- or 6-memberedheterocyclic ring which contains 1 to 3 heteroatoms such as nitrogen,oxygen and sulfur atoms instead of 1 to 3 carbon atoms in thecyclopentane ring or cyclohexane ring (e.g., pyrrolidine ring, pyrrolinering, imidazolidine ring, imidazoline ring, pyrazolidine ring,pyrazoline ring, piperidine ring, piperazine ring, morpholine ring,thiomorpholine ring, dihydrofuran ring, tetrahydrofuran ring, α-pyranering, γ-pyrane ring, dihydropyrane ring, tetrahydropyrane ring,1-thiacyclohexane ring, 1-thia-5-cyclohexene ring,1-thia-3,5-cyclohexadiene ring and the like); a 5- or 6-memberedaromatic heterocyclic ring (e.g., furan ring, thiophene ring, pyrrolering, oxazoline ring, isoxazoline ring, thiazoline ring, isothiazolinering, imidazole ring, pyrazole ring, 1,2,3-oxadiazole ring,1,2,4-oxadiazole ring, 1,3,4-oxadiazole ring, 1,2,5-oxadiazole ring,1,2,3-thiadiazole ring, 1,2,4-thiadiazole ring, 1,3,4-thiadiazole ring,1,2,3-triazole ring, 1,2,4-triazole ring, tetrazole ring, pyridine ring,pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring and thelike). Among those listed above, a pyrrolidine ring, pyrroline ring,piperazine ring, morpholine ring, thiomorpholine ring, dihydrofuranring, tetrahydrofuran ring, α-pyrane ring, γ-pyrane ring, dihydropyranering, furan ring, thiophene ring, pyrrole ring, oxazoline ring,isoxazoline ring, thiazoline ring, isothiazoline ring, imidazole ring,pyrazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring,1,3,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,2,3-thiadiazole ring,1,2,4-thiadiazole ring, 1,3,4-thiadiazole ring, 1,2,3-triazole ring,1,2,4-triazole ring are preferred, with an α-pyrane ring and furan ringbeing especially preferred.

When ring B has a further substituent in addition to -D-E-G-Ar-, thensaid substituent may, for example, be a group derivatized from anoptionally substituted cyclic hydrocarbon or an optionally substitutedheterocylic ring described above in addition to an oxo group and thioxogroup. Among those listed above, (i) a group derived from a substitutedcyclic hydrocarbon, (ii) an oxo group, (iii) a thioxo group arepreferred, with an optionally substituted phenyl group, oxo group andthioxo group being especially preferred. A substituent which may bepossessed by said phenyl group has a meaning similar to the substituentin an optionally substituted cyclic hydrocarbon described above.

A hydrocarbon group in an optionally substituted hydrocarbon grouprepresented by R¹, R², R^(2a), R³, R⁴ and R⁵ in Formula [I] describedabove may, for example, be an aliphatic linear (acyclic) hydrocarbongroup, alicyclic hydrocarbon group and aryl group, with an aliphaticlinear hydrocarbon group being preferred.

An aliphatic linear hydrocarbon group in said hydrocarbon group may be astraight or branched aliphatic hydrocarbon group such as an alkyl group,alkenyl group, alkynyl group and the like. One preferred especially is astraight or branched alkyl group. Such an alkyl may, for example, be aC₁₋₇ alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl and thelike, with a C₃₋₅ alkyl such as n-propyl, isopropyl, isobutyl, neopentylbeing preferred and isobutyl and neopentyl being especially preferred.Said alkenyl group may, for example, be a C₂₋₆ alkenyl such as vinyl,allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl,2-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 4-hexenyl, 5-hexenyl and the like, with vinyl, allyl,isopropenyl, 2-methylalllyl, 2-methyl-1-propenyl, 2-methyl-2-propenyland 3-methyl-2-butenyl being especially preferred. Said alkynyl groupmay, for example, be a C₂₋₆ alkynyl such as ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl and the like, with ethynyl, 1-propynyl and 2-propynyl beingespecially preferred.

An alicyclc hydrocarbon group in said hydrocarbon group may, forexample, be a saturated or unsaturated alicyclic hydrocarbon group suchas a cycloalkyl group, cycloalkenyl group, cycloalkadienyl group and thelike. Such a cycloalkyl group is preferably a cycloalkyl group having 3to 9 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like, with aC₃₋₆ cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl being especially preferred. Said cycloalkenyl group may, forexample, be a C₅₋₆ cycloalkenyl group such as 2-cyclopenten-1-yl,3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl,1-cyclobuten-1-yl, 1-cyclopenten-1-yl and the like. Said cycloalkadienylgroup may, for example, be a C₅₋₆ cycloalkadienyl group such as2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl.

An aryl group in said hydrocarbon group may, for example, be amonocyclic or fused polycyclic aromatic hydrocarbon group having 6 to 16carbon atoms, such as phenyl, naphthyl, anthryl, phenanthryl,acenaphthylenyl and the like, with a C₆₋₁₀ aryl group such as phenyl,1-naphtnyl and 2-naphthyl being especially preferred.

When a hydrocarbon group described above has a substituent, thesubstituent may, for example, be an optionally substituted aryl group,optionally substituted cycloalkyl group or cycloalkenyl group,optionally substituted heterocyclic group, optionally substituted aminogroup, optionally substituted hydroxyl group, optionally substitutedthiol group, acyl group, halogen atom (e.g., fluorine, chlorine,bromine, iodine and the like), oxo group, carboxyl group, nitro group,cyano group, optionally substituted alkyl group and the like, and saidhydrocarbon group may be substituted by 1 to 5 (preferably 1 to 3) ofthese optional substituents in any substitutable positions.

An aryl group in said optionally substituted aryl group may, forexample, be a C₆₋₁₆ aryl group such as phenyl, naphthyl, anthryl,phenanthryl, acenaphthylenyl and the like, with a C₆₋₁₀ aryl group suchas phenyl, 1-naphthyl and 2-naphthyl being especially preferred. Asubstituent on said aryl group may, for example, be (i) an optionallyhalogenated C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy,trifluoromethoxy and the like), (ii) a halogen atom (e.g., fluorine,chlorine, bromine, iodine), (iii) an optionally halogenated C₁₋₆ alkylgroup (e.g., methyl, ethyl, propyl, trifluoromethyl and the like), andsaid aryl group may be substituted by 1 or 2 of these optionalsubstituents.

A cycloalkyl group in said optionally substituted cycloalkyl group may,for example, be a C₃₋₇ cycloalkyl group such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and the like. The substituents onsaid cycloalkyl group and the number of the substitutions may be similarto those in the optionally substituted aryl group described above.

A cycloalkenyl group in said optionally substituted cycloalkenyl groupmay, for example, be a C₃₋₆ cycloalkenyl group such as cyclpropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl and the like. The substituentson said cycloalkenyl group and the number of the substitutions may besimilar to those in the optionally substituted aryl group describedabove.

A heterocyclic group in said optionally substituted heterocyclic groupmay, for example, be an aromatic heterocyclic group or a saturated orunsaturated non-aromatic heterocyclic group (aliphatic heterocyclicgroup), which contains at least 1, preferably 1 to 4 heteroatoms ofoxygen, sulfur and nitrogen as atoms forming the ring system (ringatoms), preferably an aromatic heterocyclic group. Said aromaticheterocyclic group may, for example, be a 5- to 6-membered aromaticmonocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl and the like) and an aromatic fusedheterocyclic group formed by condensation of two or three 5- to6-membered rings (5- to 6-membered aromatic monocyclic heterocyclic ringdescribed above, benzene ring) (e.g., benzofuranyl, isobenzofuranyl,benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnnolinyl, quinazolyl, quinoxalinyl, phtharazinyl, naphthylidinyl,purinyl, puteririnyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolidinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl and the like), with a 5- to 6-memberedaromatic monocyclic heterocyclic group such as furyl, thienyl, indolyl,isoindolyl, pyrazinyl, pyridyl and pyrimidinyl being preferred. Saidnon-aromatic heterocyclic group may, for example, be a 4- to 9-memberednon-aromatic heterocyclic group such as oxylanyl, azethidinyl, oxetanyl,thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidinyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and thelike (especially, a 5- to 9-membered cyclic amino group which maycontain 1 to 3 heteroatoms such as oxygen and sulfur atoms in additionto nitrogen atoms, specifically, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, 3,6-dihydropyridyl-1(2H)-yl and the like). Saidheterocyclic group may have 1 to 4, preferably 1 to 2 substituents, andsuch substituents may, for example, be a C₁₋₆ alkyl group (e.g., methyl,ethyl, propyl, n-butyl, n-hexyl and the like), C₆₋₁₂ aryl group (e.g.,phenyl), hydroxy-C₆₋₁₂ aryl group (e.g., 4-hydrpxyphenyl), C₁₋₄alkylsulfonyl group (e.g., methylsulfonyl), C₇₋₁₅ aralkyl group (e.g.,benzyl), C₁₋₄ alkoxy-C₁₋₄ alkyl group (for example, propoxyethyl and thelike), a 5- to 9-membered heterocyclic group which contains 1 to 3heteroatoms such as nitrogen, oxygen and sulfur atoms in addition tocarbon atoms (for example, piperidinyl, piperazinyl, morpholinyl,thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl, benzothiazolyl,benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl and the like), hyroxylgroup, oxo group, thioxo group and the like.

A substituent on said optionally substituted amino group (includingamino group, mono- or di-substituted amino group) may, for example, be alower (C₁₋₄) alkyl (e.g., methyl, ethyl, propyl and the like), a 5- to9-membered heterocyclic group which contains 1 to 3 heteroatoms such asnitrogen, oxygen and sulfur atoms in addition to carbon atoms (forexample, thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl,benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl and thelike), C₁₋₄ alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyland the like), C₆₋₁₂ aryl-carbonyl group (e.g., benzoyl and the like),C₁₋₄ alkyl-sulfonyl group, C₁₋₄ alkoxy-C₁₋₄ alkyl group and the like.When the hydrocarbon group in an optionally substituted hydrocarbongroup represented by R¹ is an alicyclic hydrocarbon group or aryl group,then the substituent may further be a C₁₋₆ alkyl group (e.g., methyl,ethyl, propyl, n-butyl, n-hexyl and the like).

Said optionally substituted hydroxyl group may, for example, be ahydroxyl group, an optionally halogenated C₁₋₁₆ alkoxy group, preferablyan optionally halogenated C₁₋₄ alkoxy group, more preferably a C₁₋₄alkoxy group (for example, methoxy, ethoxy, propoxy, butoxy, t-butoxyand the like), C₁₋₆ alkyl-carbonyloxy group (for example,methylcarbonyloxy, ethylcarbonyloxy, butylcarbonyloxy and the like),aminocarbonyloxy group, mono- or di-C₁₋₄ alkylaminocarbonyloxy group andthe like.

Said optionally substituted thiol group may, for example, be a thiolgroup, an optionally halogenated C₁₋₁₆ alkylthio group, preferably anoptionally halogenated C₁₋₄ alkylthio group, more preferably a C₁₋₄alkylthio group (for example, methylthio, ethylthio and the like), a 5-to 9-membered heterocyclic group which contains 1 to 3 heteroatoms suchas nitrogen, oxygen and sulfur atoms in addition to carbon atoms (forexample, thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl,benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl and thelike)-thio group (e.g., 2-pyridylthio) and the like.

Said acyl group may, for example, be a formyl group, C₁₋₆ alkyl-carbonylgroup, preferably C₁₋₄ alkyl-carbonyl group (e.g., methylcarbonyl,ethylcarbonyl), C₁₋₄ alkoxy-carbonyl group (e.g., mehtoxycarbonyl), C₁₋₆alkyl-sulfonyl group, preferably a C₁₋₄ alkyl-sulfonyl group (e.g.,methylsulfonyl, ethylsulfonyl), C₁₋₄ alkoxy-sulfonyl group (e.g.,methoxysulfonyl), benzyloxycarbonyl group, C₃₋₆ cycloalkyl-carbonyl,carbamoyl group, mono- or di-C₁₋₄ alkylcarbamoyl group and the like.

More specifically, substituents on said hydrocarbon group are 1 to 4substituents selected from halogen atoms; amino group; mono- or di-C₁₋₄alkylamino group; carboxyl group; C₁₋₄ alkoxycarbonyl group; hydroxylgroup; optionally halogenated C₁₋₄ alkoxy group; C₃₋₆ cycloalkyl group;nitro group; cyano group; optionally halogenated C₁₋₄ alkylthio group;cyclic amino group (for example, a 5- to 9-membered cyclic amino groupwhich may contain 1 to 3 heteroatoms such as oxygen and sulfur atoms inaddition to nitrogen atoms, specifically, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl and the like); C₁₋₄ alkyl-carbonylamino group;aminocarbonyloxy group; mono- or di-C₁₋₄ alkylaminocarbonyloxy group;C₁₋₄ alkylsulfonylamino group; C₁₋₄ alkoxy-carbonyl group;benzyloxycarbonyl group; carboxyl group; C₁₋₆ alkyl-carbonyl group; C₃₋₆cycloalkyl-carbonyl; carbamoyl group; mono- or di-C₁₋₄ alkylcarbamoylgroup; C₁₋₆ alkylsulfonyl group; C₁₋₆ alkyl group substituted by acyclic amino group which is substituted by 1 to 2 groups selected from[1] C₁₋₄ alkyl, [2] C₁₋₄ alkylsulfonyl, [3] C₆₋₁₂ aryl group which mayhave a hydroxyl group, [4] C₇₋₁₅ aralkyl group, [5] C₁₋₄ alkoxy-C₁₋₄alkyl, [6] 5- to 9-membered heterocyclic group which contains 1 to 3heteroatoms such as nitrogen, oxygen and sulfur atoms in addition tocarbon atoms, [7] hydroxyl group (for example, a 5- to 9-membered cyclicamino group which may contain 1 to 3 heteroatoms such as oxygen andsulfur atoms in addition to nitrogen atoms, specifically, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl and the like); C₁₋₆alkyl-carbonyloxy group; amino group substituted by a C₁₋₄ alkyl and a5- to 9-membered heterocyclic group which contains 1 to 3 heteroatomssuch as nitrogen, oxygen and sulfur atoms in addition to carbon atoms;amino group substituted by a C₁₋₄ alkyl and a C₁₋₄ alkyl-carbonyl; aminogroup substituted by a C₁₋₄ alkyl and a C₆₋₁₂ aryl-carbonyl; C₁₋₆alkyl-carbonyloxy group; mono- or di-C₁₋₄ alkoxy-C₁₋₄ alkyl-amino group;5- to 9-membered heterocyclic group which contains 1 to 3 heteroatomssuch as nitrogen, oxygen and sulfur atoms in addition to carbonatoms-thio group; oxo group and the like.

An optionally substituted hydroxyl group represented by R¹, R², R^(2a)and R³ in Formula [I] described above may, for example, be (i) ahydroxyl group, (ii) a C₁₋₄ alkoxy group (for example, methoxy, ethoxy,propoxy, isopropoxy, butoxy, t-butoxy and the like), (iii) a C₆₋₁₀aryloxy group (for example, phenyloxy, naphthyloxy and the like), (iv)C₁₋₄ alkyl-carbonyloxy group (for example, formyloxy, acetoxy,propionyloxy and the like), (v) a C₂₋₆ alkanoyloxy group (for example,acetyloxy, propionyloxy, valeryloxy and the like) and (vi) a C₆₋₁₀aryl-carbonyloxy group (for example, benzyloxy, naphthyloxy and thelike), with hydroxyl group and C₁₋₄ alkoxy group (for example, methoxy,ethoxy, propoxy, isopropoxy and the like) being preferred.

In Formula [I] shown above, an optionally substituted amino grouprepresented by R¹ may, for example, be an amino group which may besubstituted by 1 to 3 substituents selected from (i) a C₁₋₄ alkyl group(for example, methyl, ethyl, propyl, isopropyl and the like), (ii) aC₁₋₄ alkyl-carbonyl group (for example, acetyl, propionyl, butyryl andthe like), (iii) a C₁₋₄ alkoxy-carbonyl group (for exmaple,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like), (iv) ahalogen atom (for example, fluorine, chlorine and the like), (v) aphenyl group, (vi) a C₁₋₄ alkyl-phenyl group (for example,4-methylphenyl, 3-methylphenyl, 2-methylphenyl and the like), (vii) ahalogenated phenyl group (for example, 4-chlorophenyl, 3-chlorophenyl,2-chlorophenyl and the like), and (viii) a C₁₋₄ alkoxy-phenyl group (forexample, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl and thelike), with an amino group and a mono- or di-C₁₋₄ alkylamino group (forexample, methylamino, ethylamino, propylamino, dimethylamino,diethylamino and the like) being especially preferred.

In Formula [I] shown above, a mercapto group which may be substituted byan optionally substituted hydrocarbon group represented by R³ may, forexample, be a mercapto group which may be substituted by an optionallysubstituted hydrocarbon group similar to the optionally substitutedhydrocarbon group described above, and among these a C₁₋₄ alkylthiogroup (for example, methylthio, ethylthio, propylthio and the like) isespecially preferred.

In Formula [I] shown above, a C₁₋₃ alkylene group in a C₁₋₃ alkylenegroup which may be substituted by an oxo group or thioxo grouprepresented by D may, for example, be —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂— and—CH(CH₃)—CH₂— and the like, with —CH₂— and —CH₂CH₂— being preferred.

Said C₁₋₃ alkylene group substituted by an oxo group or thioxo groupmay, for example, be —CO—, —CS—, —CH₂CO—, —CH₂CS—, —CH₂CH₂CO—,—CH₂CH₂CS— and the like.

D is preferably (i) a C₁₋₃ alkylene group which may be substituted by anoxo group, (ii) —NH—, (iii) —CH₂NH—, and those preferred especially are—CH₂—, —CH₂CO—, —CH₂CH₂CO—, —NH—.

In Formula [I] shown above, when D is taken together with a constituentatom of the ring B to form a 5- to 7-membered ring which may besubstituted by an oxo group or thioxo group, then a preferred example ofsaid 5- to 7-membered ring is a 5- to 7-membered saturated heterocyclicring containing 1 to 3 nitrogen atoms which may be substituted by an oxogroup or thioxo group where a constituent atom of the ring B adjacent tothe constituent atom of the ring B to which D is attached is takentogether, with a 5- or 6-membered saturated heterocyclic ring containingone nitrogen atom being especially preferred.

A typical preferred example when D is taken together with a constituentatom of the ring B to form a 5- to 7-membered ring which may besubstituted by an oxo group or thioxo group is represented by Formula:

wherein ring M^(a) may be substituted by an oxo group or thioxo group; his an integer of 3 to 5; other symbols are as defined above, preferablyrepresented by Formula:

wherein ring M^(a′) may be substituted by an oxo group; other symbolsare as defined above.

A preferred example of E in Formula [I] shown above is —NR^(4′)— (inwhich R^(4′) is a hydrogen atom or a C₁₋₆ alkyl such as methyl, ethyl,n-propyl, n-butyl, isopropyl, hexyl and the like, which may besubstituted), —CONR^(5′)— (in which R^(5′) is a hydrogen atom or a C₁₋₆alkyl such as methyl, ethyl, n-propyl, n-butyl, isopropyl, hexyl and thelike, which may be substituted). The substituent which may be possessedby said R^(4′) and R^(5′) may be similar to the substituent which may bepossessed by an optionally substituted hydrocarbon group describedabove. More preferably, E is —CONR^(5′—) (in which R^(5′) is a hydrogenatom or a C₁₋₆ alkyl such as methyl, ethyl, n-propyl, n-butyl,isopropyl, hexyl and the like, which may be substituted).

In Formula [I] shown above, when R⁴ is taken together with a constituentatom of the ring B to form a 5- to 7-membered ring which may besubstituted by an oxo group or thioxo group, then a preferred example ofsaid 5- to 7-membered ring is a 5- to 7-membered saturated heterocyclicring containing 2 to 4 nitrogen atoms which may be substituted by an oxogroup or thioxo group where a constituent atom of the ring B adjacent tothe constituent atom of the ring B to which R⁴ is attached is takentogether, with a 5- or 6-membered saturated heterocyclic ring containingtwo nitrogen atoms being especially preferred.

A typical preferred example when R⁴ is taken together with a constituentatom of the ring B to form a 5- to 7-membered ring which may besubstituted by an oxo group or thioxo group is represented by Formula:

wherein ring M^(b) may be substituted by an oxo group or thioxo group; iis an integer of 1 to 3; provided that the total number of carbon atomsin the constituent atoms of D and —(CH₂)i- is 2 to 4; and other symbolsare as defined above, preferably represented by Formula:

wherein D^(a) and E^(a) are —CH₂— or —CO—; and other symbols are asdefined above.

In Formula [I] shown above, a C₁₋₃ alkylene group represented by G may,for example, be methylene, ethylene, propylene and the like.

Preferred examples of D, E and G are the combinations in which (i) D is—CO—, E is —NR⁴— (in which R⁴ is as defined above), G is —CH₂— or—CH₂CH₂—; (ii) D is —CO—, E is —NR⁴— (in which R⁴ is as defined above),G is a bond; (iii) D is —CH₂CO— or —CH₂CH₂CO—, E is —NR⁴— (in which R⁴is as defined above), G is a bond; (iv) D is —CH₂CO— or —CH₂CH₂CO—, E is—NR⁴— (in which R⁴ is as defined above), G is —CH₂— or —CH₂CH₂—; (v) Dis —CH₂— or —CH₂CH₂—, E is —O—, G is —CH₂— or —CH₂CH₂—; (vi) D is —CH₂—or —CH₂CH₂—, E is —NR⁴— (in which R⁴ is as defined above), G is —CH₂— or—CH₂CH₂—; (vii) D is —NH—, E is —COR⁵— (in which R⁵ is as definedabove), G is a bond and (viii) D is —CH₂— or —CH₂CH₂—, E is —S— or —SO—,G is —CH₂— or —CH₂CH₂—.

In Formula [I] shown above, Ar represents an optionally substituted arylgroup or optionally substituted heterocyclic group. An aryl group in anoptionally substituted aryl group represented by Ar is preferably aC₆₋₁₀ aryl group such as phenyl and naphthyl, with a phenyl group beingespecially preferred. Such an aryl group represented by Ar may contain 1to 5, preferably 1 to 3 same or different substituents. The substitutionmay occur in any position in the ring. Such a substituent may, forexample, be (i) an optionally halogenated C₁₋₄ alkyl group (for example,methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl, isopropyl,3,3,3-trifluoropropyl, butyl and the like), (ii) a C₁₋₄ alkylsubstituted by an amino group (for example, aminomethyl, 2-aminoethyland the like), (iii) a C₁₋₄ alkyl group substituted by a mono- ordi-C₁₋₄ alkylamino group (for example, methylaminomethyl,dimethylaminomethyl, 2-methylaminoethyl, 2-dimethylaminoethyl and thelike), (iv) a C₁₋₄ alkyl group substituted by a carboxyl group (forexample, carboxymethyl, carboxyethyl and the like), (v) a C₁₋₄ alkylgroup substituted by a C₁₋₄ alkoxycarbonyl group (for example,methoxycarbonylethyl, ethoxycarbonylethyl and the like), (vi) a C₁₋₄alkyl group substituted by a hydroxy group (for example, hydroxymethyl,hydroxyethyl and the like), (vii) a C₁₋₄ alkyl group substituted by aC₁₋₄ alkoxycarbonyl group (for example, methoxymethyl, methoxyethyl,ethoxyethyl and the like), (viii) a C₃₋₆ cycloalkyl group (for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), (ix) ahalogen atom (for example, fluorine, chlorine, bromine, iodine and thelike), (x) a nitro group, (xi) a cyano group, (xii) a hydroxyl group,(xiii) an optionally halogenated C₁₋₄ alkoxy group (for example,methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propyloxy, butoxy, isopropyloxy and the like),(xiv) an optionally halogenated C₁₋₄ alkylthio group (for example,methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio and the like), (xv) an amino group,(xvi) a mono- or di-C₁₋₄ alkylamino group (for example, methylamino,ethylamino, propylamino, dimethylamino, diethylamino and the like),(xvii) a cyclic amino group (for example, 5- to 9-membered cyclic aminogroup which may contain 1 to 3 heteroatoms such as oxygen and sulfuratoms in addition to nitrogen atoms, specifically, pyrrolidino,pyperidino, morpholino and the like); (xviii) a C₁₋₄ alkyl-carbonylaminogroup (for example, acetylamino, propionylamino, butyrylamino and thelike), (xix) an aminocarbonyloxy group, (xx) a mono- or di-C₁₋₄alkylaminocarbonyloxy group (for example, methylaminocarbonyloxy,ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxyand the like), (xxi) a C₁₋₄ alkylsulfonylamino group (for example,methylsulfonylamino, ethylsulfonylamino, propylsulfomylamino and thelike), (xxii) a C₁₋₄ alkoxy-carbonyl group (for example,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl andthe like), (xxiii) a benzyloxycarbonyl group, (xxiv) a carboxyl group,(xxv) a C₁₋₆ alkyl-carbonyl group (for example, methylcarbonyl,ethylcarbonyl, butylcarbonyl and the like), (xxvi) a C₃₋₆cycloalkyl-carbonyl (for example, cyclohexylcarbonyl and the like),(xxvii) a carbamoyl group, (xxviii) a mono- or di-C₁₋₄ alkylcarbamoylgroup (for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl and the like) and(xxix) a C₁₋₆ alkylsulfonyl group (for example, methylsulfonyl,ethylsulfonyl, propylsulfonyl and the like), as well as an optionallysubstituted heterocyclic group represented by Ar described below whichmay itself be employed as a substituent on the aryl group. Such anoptionally substituted heterocyclic group may, for example, be a 5- or6-membered aromatic monocyclic heterocyclic group (for example, furyl,thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl and the like) which may be substitutedby 1 to 3 substituents selected from (i) an optionally halogenated C₁₋₄alkyl group (for example, methyl, chloromethyl, difluoromethyl,trichloromethyl, trifluoromethyl, ethyl, 2-buromoethyl,2,2,2-trifluoroethyl, propyl, isopropyl, 3,3,3-trifluoropropyl, butyland the like), (ii) a C₃₋₆ cycloalkyl group (for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like), (iii) a halogen atom(e.g., fluorine, chlorine, bromine, iodine and the like), (iv) ahydroxyl group, (v) an optionally halogenated C₁₋₄ alkoxy group (forexample, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propyloxy, butyloxy, isopropyloxy and the like,(vi) an optionally halogenated C₁₋₄ alkylthio group (for example,methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio and the like), (vii) an aminogroup, (viii) a mono- or di-C₁₋₄ alkylamino group (for example,methylamino, ethylamino, propylamino, dimethylamino, diethylamino andthe like), (ix) a C₁₋₄ alkoxy-carbonyl group (for example,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl andthe like), (x) a carboxyl group and a C₁₋₆ alkyl-carbonyl group (forexample, methylcarbonyl, ethylcarbonyl, butylcarbonyl and the like).

Preferred among the substituents listed above are (i) an optionallyhalogenated C₁₋₄ alkyl group (for example, methyl, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, propyl, isopropyl, 3,3,3-trifluoropropyl and thelike), (ii) a halogen atom (for example, fluorine, chlorine, bromine andthe like), (iii) a nitro group, (iv) a hydroxyl group, (v) an optionallyhalogenated C₁₋₄ alkoxy group (for example, methoxy, difluoromethoxy,trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy and the like), (vi) anamino group, (vii) a C₁₋₄ alkyl group substituted by a mono- or di-C₁₋₄alkylamino group (for example, methylaminomethyl, dimethylaminomethyl,2-methylaminoethyl, 2-dimethylaminoethyl and the like), (viii) a mono-or di-C₁₋₄ alkylamino group (for example, methylamino, ethylamino,dimethylamino, diethylamino and the like), (ix) a C₁₋₄ alkoxy-carbonylgroup (for example, methoxycarbonyl, ethoxycarbonyl and the like), (x) acarboxyl group and (xi) a carbamoyl group, with an optionallyhalogenated C₁₋₄ alkyl group (for example, methyl, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,propyl, isopropyl and the like), a halogen atom (for example, fluorine,chlorine, bromine and the like) and an optionally halogenated C₁₋₄alkoxy group (for example, methoxy, trifluoromethoxy, ethoxy, propoxyand the like) being especially preferred.

In Formula [I] shown above, a heterocyclic group in an optionallysubstituted heterocyclic group represented by Ar may, for example, be a5- to 9-membered, preferably 5- or 6-membered aromatic heterocyclicgroup having 1 to 4, preferably 1 to 2 heteroatoms such as nitrogen,oxygen and sulfur atoms in addition to carbon atoms.

Such an aromatic heterocyclic group may, for example, be an aromaticmonocyclic heterocyclic group such as furyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl and the like, or an aromatic fusedheterocyclic group such as benzofuranyl, isobenzofuranyl,benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnnolinyl, quinazolyl, quinoxalinyl, phtharazinyl, naphthylidinyl,purinyl, puteririnyl, α-carbazolyl, β-carbolinyl, carbolinyl,γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolidinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl and the like.

Among the heterocyclic groups described above, a 5- or 6-memberedheterocyclic group is preferred, and those employed preferably arefuryl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl,pyridyl, pyrimidinyl, pyridazinyl, quinolyl, isoquinolyl, thiazolyl,thiadiazolyl, thiophenyl and the like. Furyl, thienyl and pyridyl areespecially preferred.

A substituent which may be possessed by an optionally substitutedheterocyclic group represented by Ar may, for example, be (i) anoptionally halogenated C₁₋₄ alkyl group (for example, methyl,chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,2,2-dibromoethyl, 2,2,2-trifluoroethyl, propyl, isopropyl,3,3,3-trifluoropropyl, butyl and the like), (ii) a C₃₋₆ cycloalkyl group(for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and thelike), (iii) a halogen atom (for example, fluorine, chlorine, bromine,iodine and the like), (iv) a nitro group, (v) a cyano group, (vi) ahydroxyl group, (vii) an optionally halogenated C₁₋₄ alkoxy group (forexample, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy,ethoxy, 2,2,2-trifluoroethoxy, propyloxy, butyloxy, isopropyloxy and thelike), (viii) an optionally halogenated C₁₋₄ alkylthio group (forexample, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio and the like), (ix) an amino group,(x) a mono- or di-C₁₋₄ alkylamino group (for example, methylamino,ethylamino, propylamino, dimethylamino, diethylamino and the like), (xi)a cyclic amino group (for example, a 5- to 9-membered cyclic amino groupwhich may contain 1 to 3 heteroatoms such as oxygen and sulfur atoms inaddition to nitrogen atoms, specifically, pyrrolidino, piperidino,morpholino and the like), (xii) a C₁₋₄ alkyl-carbonylamino group (forexample, acetylamino, propionylamino, butyrylamino and the like), (xiii)an aminocarbonyloxy group, a mono- or di-C₁₋₄ alkylaminocarbonyloxygroup (for example, methylaminocarbonyloxy, ethylaminocarbonyloxy,dimethylaminocarbonyloxy, diethylaminocarbonyloxy and the like), (xiv) aC₁₋₄ alkylsulfonylamino group (for example, methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino and the like), (xv) a C₁₋₄alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isobutoxycarbonyl and the like), (xvi) a carboxylgroup, (xvii) a C₁₋₆ alkyl-carbonyl group (for example, methylcarbonyl,ethylcarbonyl, butylcarbonyl and the like), (xviii) a C₃₋₆cycloalkylcarbonyl group (for example, cyclohexylcarbonyl and the like),(xix) a carbamoyl group, a mono- or di-C₁₋₄ alkylcarbamoyl group (forexample, methylcarbamoyl, ehtylcarbamoyl, propylcarbamoyl,butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl and the like), (xx) aC₁₋₆ alkylsulfonyl group (for example, methylsulfonyl, ethylsulfonyl,propylsulfonyl and the like), (xxi) a C₃₋₆ cycloalkylsulfonyl (forexample, cyclopentylsulfonyl, cyclohexylsulfonyl and the like), (xxii) aphenyl, naphthyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl-C₁₋₄alkylcarbamoyl, phenylcarbamoyl, phenyl-C₁₋₄ alkyl-carbonylamino,benzoylamino, phenyl-C₁₋₄ alkylsulfonyl, phenylsulfonyl, phenyl-C₁₋₄alkylsulfinyl, phenyl-C₁₋₄ alkylsulfonylamino or phenylsuofonylamino andthe like, whose phenyl or naphthyl group may be substituted by 1 to 3substituents selected from C₁₋₄ alkyl group such as methyl, ethyl,propyl, butyl and isopropyl, C₁₋₄ alkoxy group such as methoxy, ethoxy,n-propyloxy, i-propyloxy and n-butyloxy, halogen atom such as chloro,bromo and iodo, hydroxyl group, benzyloxy group, amino group, mono- ordi-C₁₋₄ alkylamino group, nitro group, C₁₋₆ alkylcarbonyl group and thelike.

Among those listed above, preferred substituents may, for example, be(i) a halogen atom (for example, fluorine, chlorine, bromine and thelike), (ii) an optionally halogenated C₁₋₄ alkyl group (for example,methyl, chloromethyl, difluoromethyl, trifluoromethyl, ethyl, propyl,isopropyl and the like), (iii) a C₃₋₆ cycloalkyl group (for example,cyclopropyl, cyclobutyl and the like), (iv) a hydroxyl group, (v) anoptionally halogenated C₁₋₄ alkoxyl group (for example, methoxy,difluoromethoxy, trifluoromethoxy, ethoxy and the like), (vi) anoptionally halogenated C₁₋₄ alkylthio group (for example, methylthio,trifluorothio, ethylthio and the like), (vii) an amino group, (viii) amono- or di-C₁₋₄ alkylamino group (for example, methylamino, ethylamino,dimethylamino, diethylamino and the like), (ix) a C₁₋₄ alkoxy-carbonylgroup (for example, methoxycarbonyl, ethoxycarbonyl and the like) and(x) a carboxyl group and the like, with a halogen atom (for example,fluoro, chloro and the like), C₁₋₄ alkyl (for example, methyl, ethyl andthe like), C₃₋₆ cycloalkyl group (for example, cyclopropyl, cyclobutyland the like), hydroxyl group, C₁₋₄ alkoxy group (for example, methoxy,ethoxy and the like) and carboxyl group being especially preferred.

Ar is preferably a phenyl group which may be substituted by 1 to 3substituents selected from halogen atoms (for example, fluorine,chlorine and the like), an optionally halogenated C₁₋₄ alkyl group (forexample, methyl, difluoromethyl, trifluoromethyl, ethyl,2,2,2-trifluoroethyl, propyl, isopropyl and the like) and an optionallyhalogenated C₁₋₄ alkoxy group (for example, methoxy, difluoromethoxy,trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy andthe like). A 5- to 6-membered heterocyclic group containing 1 to 3heteroatoms (for example, nitrogen atoms, oxygen atoms, sulfur atoms andthe like) other than carbon atoms (for example, furyl, pyridyl,pyrimidinyl, thienyl, thiazolyl, thiadiazolyl and the like) which may besubstituted by a substituent selected from an optionally halogenatedC₁₋₄ alkyl group (for example, methyl, trifluoromethyl, ethyl and thelike), C₁₋₄ alkoxy group (for example, methoxy, ethoxy, propoxy and thelike) and C₃₋₆ cycloalkyl (for example, cyclopropyl and the like) isalso preferred.

One especially preferred as Ar may, for example, be a phenyl group orpyridyl group which may be substituted by 1 to 4 substituents selectedfrom halogen atoms (for example, chlorine, fluorine and the like),optionally halogenated C₁₋₄ alkyl group (for example, methyl,trifluoromethyl, ethyl, isopropyl and the like), optionally halogenatedC₁₋₄ alkoxy group (for example, methoxy, trifluoromethoxy, ethoxy andthe like), di-C₁₋₄ alkylamino group (for example, dimethylamino and thelike), C₁₋₃ acyloxy group (for example, acetoxy and the like) andhydroxyl group.

A preferred compound represented by Formula [I] or a salt thereof may,for example, be a compound represented by Formula [II]:

in which ring A′ is an optionally substituted 6-membered hydrocarbongroup; ring C is an optionally substituted benzene group; one of X′ andZ is —NR^(1′)— (in which R^(1′) is a hydrogen atom, optionallysubstituted hydrocarbon group or optionally substituted amino group),—O— or —S— and the other is —CO—, —CS— or —C(R^(2′))R^(2a′)— (in whicheach of R^(2′) and R^(2a′) is a hydrogen atom or optionally substitutedhydrocarbon group), or one of them is —N═ and the other is ═CR^(3′)— (inwhich R^(3′) is a hydrogen atom, halogen atom, optionally substitutedhydrocarbon group, optionally substituted amino group, optionallysubstituted hydroxyl group or a mercapto group which may be substitutedby an optionally substituted hydrocarbon group);

is a single bond or double bond; Y′, when

adjacent to Y′ is a single bond, is

(in which R⁶ is a hydrogen atom, hydroxyl group or optionallysubstituted hydrocarbon group) or a nitrogen atom, Y′, when

adjacent to Y′ is a double bond, is a carbon atom; D′ is a C₁₋₃ alkylenegroup which may be substituted by an oxo group or thioxo group; E′ is—NR⁷— (in which R⁷ is a hydrogen atom or optionally substitutedhydrocarbon group), —O— or —S(O)n- (in which n is 0, 1 or 2); G′ is abond or C₁₋₃ alkylene group; Ar′ is an optionally substituted aryl groupor optionally substituted heterocyclic group, D′ may be taken togetherwith Z′ to form a 5- to 7-membered ring which may be substituted by anoxo group or thioxo group, R⁷ may be taken together with Z to form a 5-to 7-membered ring which may be substituted by an oxo group or thioxogroup, or a salt thereof.

In Formula [II] shown above, a substituent which may be possessed byring A′ and ring C has a meaning similar to the substituent which may bepossessed by an optionally substituted cyclic hydrocarbon represented byring A in Formula [I] shown above.

In Formula [II] shown above, “an optionally substituted hydrocarbongroup”, “an optionally substituted amino group”, “an optionallysubstituted hydroxyl group”, “mercapto group which may be substituted byan optionally substituted hydrocarbon group”, “C₁₋₃ alkylene group whichmay be substituted by an oxo group or thioxo group”, “C₁₋₃ alkylenegroup”, “an optionally substituted aryl group or optionally substitutedheterocyclic group” have the meanings similar to those described above.

“A 5- to 7-membered ring which may be substituted by an oxo group orthioxo group” formed by D′ taken together with Z has the meaning similarto “a 5- to 7-membered ring which may be substituted by an oxo group orthioxo group” formed by D taken together with a constituent atom of thering B.

“A 5- to 7-membered ring which may be substituted by an oxo group orthioxo group” formed by R⁷ taken together with Z has the meaning similarto “a 5- to 7-membered ring which may be substituted by an oxo group orthioxo group” formed by R⁴ taken together with a constituent atom of thering B.

Another preferred example of a compound represented by Formula [I] or asalt thereof may, for example, be a compound represented by Formula[III]:

in which each of ring A″, ring C′ and ring D is an optionallysubstituted benzene ring, X″ is —NR⁸— (in which R⁸ is a hydrogen atom oroptionally substituted hydrocarbon group), —O— or —S—, U is —(CH₂)m- (inwhich m is 1 or 2) or —NH—, R^(a) is a hydrogen atom or optionallysubstituted hydrocarbon group), or a salt thereof.

In Formula [III] shown above, a substituent which may be possessed byrings A″, C′ or D has a meaning similar to the substituent which may bepossessed by an optionally substituted cyclic hydrocarbon represented byring A in Formula [I] shown above.

In Formula [III] shown above, “an optionally substituted hydrocarbongroup” has the meaning similar to that described above.

A further preferred example of a compound represented by Formula [I] ora salt thereof may, for example, be a compound represented by Formula[IV]:

in which ring A″′ is an optionally substituted benzene ring, Q is anoptionally substituted aromatic ring, W is —CH₂—, —CO— or —CS—, V is

or W and V are taken together to form

Y″ is —CH₂—, —O—, —S—, —CO—, —CS— or —NR⁹ (in which R⁹ is a hydrogenatom or hydrocarbon group), U′ is —NH—, —CH₂— or —CH₂NH—, R^(b) is ahydrogen atom or optionally substituted hydrocarbon group,

is a single bond or double bond, or a salt thereof.

Ring A″′ represents an optionally substituted benzene ring, and ring Qrepresents an optionally substituted aromatic ring. A substituent onsuch a benzene ring and aromatic ring may, for example, be (i) a halogenatom (for example, fluorine, chlorine, bromine, iodine and the like,preferably chlorine and fluorine), (ii) an alkyl group which may besubstituted by a halogen, (iii) an alkoxy group which may be substitutedby a halogen, (iv) an alkylthio group which may be substituted by ahalogen, (v) a C₁₋₇ acylamino group (for example, a C₁₋₆ alkanoylaminogroup such as formylamino, acetylamino, propionylamino and butyrylamino,as well as benzoylamino group and the like), (vi) an amino group whichmay be substituted by a C₁₋₄ alkylamino group (for example, a mono- ordi-C₁₋₄ alkylamino group such as methylamino, ethylamino, propylamino,dimethylamino, methylethylamino and methylpropylamino), (vii) a C₁₋₃acyloxy group (for example, formyloxy, acetoxy, propionyloxy group andthe like), (viii) a hydroxyl group, (ix) a cyano group, (x) a carboxylgroup and the like.

An alkyl group which may be substituted by a halogen described abovemay, for example, be a straight or branched alkyl group having 1 of 6carbon atoms unsubstituted or substituted by 1 to 5 halogen atoms (forexample, fluorine, chlorine, bromine, iodine and the like, preferably,chlorine and bromine), and those employed widely are methyl,chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,2-buromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl,3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, 5,5,5-trifluoropentyl, 4-trifluoromethylbutyl,hexyl, 6,6,6-trifluorohexyl, 5-trifluoromethylpentyl and the like, witha straight or branched alkyl group having 1 to 4 carbon atomsunsubstituted or substituted by 1 to 3 halogen atoms described abovebeing employed preferably, including methyl, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl,2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl,sec-butyl, tert-butyl and the like.

An alkoxy group which may be substituted by a halogen and an alkylthiogroup which may be substituted by a halogen are an alkoxy group whichmay be substituted by a halogen and an alkylthio group which may besubstituted by a halogen formed by binding an alkyl group or ahalogen-substituted alkyl group described above with an oxygen atom anda sulfur atom, respectively.

An alkoxy group which may be substituted by a halogen may, for example,be a straight or branched alkoxy group having 1 to 6 carbon atomsunsubstituted or substituted by 1 to 5 halogen atoms as described above,and those employed widely are methoxy, difluoromethoxy,trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy, hexyloxyand the like, with a straight or branched alkoxy group having 1 to 4carbon atoms unsubstituted or substituted by 1 to 3 halogen atoms asdescribed above being employed preferably, including methoxy,difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy,sec-butoxy and the like.

An alkylthio group which may be substituted by a halogen may, forexample, be a straight or branched alkylthio group having 1 to 6 carbonatoms unsubstituted or substituted by 1 to 5 halogen atoms as describedabove, and those employed widely are methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like, with astraight or branched alkylthio group having 1 to 4 carbon atomsunsubstituted or substituted by 1 to 3 halogen atoms as described abovebeing employed preferably, including methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio and the like.

The expression “which may be substituted by a halogen” hereinafter meansthat 1 to 3 halogens may be possessed as described above.

A preferred substituent on a benzene ring represented by ring A″′ and onan aromatic ring represented by ring Q is (i) a halogen atom, (ii) aC₁₋₆ alkyl group which may be substituted by a halogen, (iii) a C₁₋₆alkoxy group, (iv) a hydroxy group, (v) an amino group which may besubstituted by a C₁₋₄ alkyl group and (vi) a C₁₋₃ acyloxy group. Each ofthe terms (i) to (vi) has the meaning described above.

A substituent on a benzene ring represented by ring A″′ and on anaromatic ring represented by ring Q may be present in any substitutableposition on the benzene ring and the aromatic ring, and when thesubstitution occurs twice or more, then the substituents may be same ordifferent, and the number of the substituents may be 1 to 4, preferably2 or 3. It is also possible that adjacent carbon atoms on the ring A orthe ring Q are taken together with —(CH₂)₄— (q is an integer of 3 to 5)to form a 5- to 7-membered ring, and such a case is also encompassed inthe compound represented by Formula [III].

As ring A, a benzene ring substituted by 1 to 4 substituents selectedfrom a halogen (for example, chlorine), C₁₋₄ alkyl group which may besubstituted by 1 to 3 halogens (for example, methyl, ethyl, isopropyl,trifluoromethyl and the like) and C₁₋₄ alkoxy group (for example,methoxy and the like) is employed, with a benzene ring substituted by asingle halogen (having the meaning described above) or a single C₁₋₄alkyl group (for example, methyl, ethyl, isopropyl and the like) beingpreferred.

An aromatic ring represented by ring Q may, for example, be a 5- or6-membered aromatic ring which may have 1 to 4, preferably 1 to 2oxygen, sulfur or nitrogen atoms in addition to carbon atoms, preferablya 5- or 6-membered aromatic ring which may have 1 or 2 nitrogen atoms inaddition to carbon atoms, more preferably, (1) a benzene ring, (2) apyridine ring, (3) a pyrazine ring, (4) a pyrimidine ring, (5) apyridazine ring and the like, still preferably a benzene ring orpyrimidine ring, especially a benzene ring.

Ring Q may have same or different 1 to 4 substituents, and suchsubstituents are preferably (i) halogens (for example, fluorine,chlorine and the like), (ii) a C₁₋₄ alkyl group which may be substitutedby a halogen (for example, methyl, ethyl, isopropyl, trifluoromethyl andthe like), (iii) a C₁₋₄ alkoxy group which may be substituted by ahalogen (for example, methoxy, ethoxy, isopropoxy, trifluoromethoxy andthe like), (iv) a di-C₁₋₄ alkylamino group (for example, dimethylaminogroup and the like), (v) a C₁₋₃ acyloxy group (for example, acetoxygroup) or (vi) a hydroxyl group, especially halogens (having the meaningdescribed above), a C₁₋₄ alkyl group (having the meaning describedabove) which may be substituted by a halogen, a C₁₋₄ alkoxy group(having the meaning described above) which may be substituted by ahalogen.

In Formula [III] described above, an optionally substituted hydrocarbongroup represented by R^(b) has the meaning described above.

A hydrocarbon group represented by R⁹ has the meaning described above.

In Formula [IV] shown above, W is —CH₂—, —CO— or —CS—, preferably —CH₂—,—CO—.

In Formula [IV] shown above, V is

or W and V are taken together to form

preferably, V is

In Formula [IV] shown above, Y″ is —CH₂—, —O—, —S—, —CO—, —CS— or —NR⁹—(in which R⁹ has the meaning described above), preferably, —CH₂—, —O—,—CO—, —NR^(9a)— (in which R^(9a) is a C₁₋₆ alkyl group such as methyl,ethyl, propyl, isopropyl and the like), with —CH₂—, —O— being especiallypreferred.

In Formula [IV] shown above, U′ is —NH—, —CH₂—, —CH₂NH—, preferably—NH—, —CH₂—.

Another preferred example of a compound represented by Formula [I] may,for example, be a compound represented by Formula [V]:

in which each of R¹⁰ and R¹¹ is a hydrogen atom, halogen atom,optionally substituted linear hydrocarbon group or the both may be takentogether with the adjacent carbon atoms to form an optionallysubstituted cyclic hydrocarbon group or a dihydrofuran ring which may besubstituted by an oxo group, ring I is an optionally substituted benzenering or optionally substituted pyridine ring, ring J is an optionallysubstituted benzene ring or optionally substituted pyridine ring(preferably, when R¹⁰ is a hydrogen atom, then R¹¹ is a substitutedlinear hydrocarbon group), or a salt thereof, and each of R¹⁰ and R¹¹ ispreferably a hydrogen atom, halogen atom or optionally substitutedlinear hydrocarbon group or the both may be taken together with theadjacent carbon atoms to form an optionally substituted cyclichydrocarbon group or a dihydrofuran ring which may be substituted by anoxo group.

“Linear hydrocarbon group” in “an optionally substituted linearhydrocarbon group” and “hydroxyl group which may be substituted by anoptionally substituted linear hydrocarbon group” represented by R¹⁰ andR¹¹ in Formula [V] shown above may, for example, be an alkyl group,alkenyl group and alkynyl group.

An alkyl group is a straight or branched group having 1 to 7 carbonatoms, preferably a straight or branched group having 1 to 4 carbonatoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl and the like.

An alkenyl group is an alkenyl group having 2 to 6 carbon atoms, such asethenyl, propenyl, isopropenyl, butenyl, isobutenyl, sec-butenyl and thelike, preferably an alkenyl group having 2 to 4 carbon atoms, such asethenyl, propenyl, isopropenyl and the like.

An alkynyl group is an alkynyl group having 2 to 6 carbon atoms, such asethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl and thelike, preferably an alkynyl group having 2 to 4 carbon atoms, such asethynyl, propynyl, isopropynyl and the like.

A linear hydrocarbon group described above is preferably a straight orbranched alkyl group having 1 to 6 carbon atoms, especially a straightor branched alkyl group having 1 to 4 carbon atoms such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and thelike.

A substituent on “an optionally substituted linear hydrocarbon group”and “hydroxyl group which may be substituted by an optionallysubstituted linear hydrocarbon group” represented by R¹⁰ and R¹¹ may bea substituent in “an optionally substituted linear hydrocarbon group”described above.

Each of R¹⁰ and R¹¹-may, for example, be a halogen atom (e.g., fluorineatom, chlorine atom, bromine atom), optionally substituted C₁₋₇ alkylgroup (preferably a C₁₋₄ alkyl group, such as methyl, ethyl and propyl,especially methyl), optionally substituted C₂₋₆ alkenyl group (forexample, ethenyl) or hydroxyl group which may be substituted by anoptionally substituted C₁₋₇ alkyl group (preferably, hydroxyl group,C₁₋₄ alkoxy group such as methoxy), with a halogen atom or an optionallysubstituted C₁₋₇ alkyl being preferred. “A C₁₋₇ alkyl group” in “anoptionally substituted C₁₋₇ alkyl group” has an oxo group as asubstituent, and when said oxo group is present in an α-position, then aC₁₋₇ alkanoyl group such as formyl and acetyl may be formed.

A preferred substituent on a C₁₋₇ alkyl group described above may forexample be:

-   (i) a hydroxyl group,-   (ii) a mono- or di-C₁₋₄ alkylamino group (e.g., dimethylamino,    diethylamino),-   (iii) an amino group substituted by a C₁₋₄ alkyl and a 5- to    9-membered heterocyclic group which contains 1 to 3 heteroatoms such    as nitrogen, oxygen and sulfur atoms in addition to carbon atoms    (for example, thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl,    benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl and    the like) (e.g., methyl(2-pyridyl)amino),-   (iv) an amino group substituted by a C₁₋₄ alkyl and a C₁₋₄    alkyl-carbonyl (e.g., methyl(methylcarbonyl)amino),-   (v) an amino group substituted by a C₁₋₄ alkyl and a C₆₋₁₂    aryl-carbonyl (e.g., methyl(benzoyl)amino),-   (vi) a mono- or di-C₁₋₄ alkoxy-C₁₋₄ alkyl-amino group (e.g.,    butoxypropylamino),-   (vii) 5- to 9-membered cyclic amino group which may contain 1 to 3    heteroatoms such as oxygen and sulfur atoms in addition to nitrogen    atoms (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,    3,6-dihydropyridin-1(2H)-yl), optionally substituted by a C₆₋₁₂ aryl    which may have 1 to 4 substituents selected from a C₁₋₄ alkyl (e.g.,    methyl), halogen atoms, hydroxy group and optionally halogenated    C₁₋₄ alkyl (e.g., phenyl, 4-hydroxyphenyl, 4-chlorophenyl,    3-methylphenyl), C₁₋₄ alkylsulfonyl (e.g., methylsulfonyl), C₇₋₁₅    aralkyl (e.g., benzyl) which may have 1 to 4 substituents selected    from, halogen atoms, hydroxy group and optionally halogenated C₁₋₄    alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl (for example, propoxyethyl and the    like), 5- to 9-membered heterocyclic group which contains 1 to 3    heteroatoms such as nitrogen, oxygen and sulfur atoms in addition to    carbon atoms (for example, piperidinyl, piperazinyl, morpholinyl,    thienyl, furyl, pyridyl, pyrimidinyl, thiazolyl, benzothiazolyl,    benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl and the like),    hydroxyl group and the like,-   (viii) a C₁₋₆ alkyl-carbonyloxy group (for example,    methylcarbonyloxy, ethylcarbonyloxy, butylcarbonyloxy and the like),-   (ix) a 5- to 9-membered heterocyclic group which contains 1 to 3    heteroatoms such as nitrogen, oxygen and sulfur atoms in addition to    carbon atoms (for example, thienyl, furyl, pyridyl, pyrimidinyl,    thiazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl,    benzoisoxazolyl and the like)-thio group (e.g., 2-pyridylthio) and    the like.

A preferred substituent on said C₂₋₆ alkenyl group may, for example, bea C₁₋₄ alkoxy-carbonyl (e.g., methoxycarbonyl) and the like.

A cyclic hydrocarbon when R¹⁰ and R¹¹ in Formula [V] shown above aretaken together with the adjacent carbon atoms to form an optionallysubstituted cyclic hydrocarbon may, for example, be a saturated orunsaturated cyclic aliphatic hydrocarbon (for example, cycloalkane,cycloalkene, cycloalkadiene and the like) and aryl. Such a cycloalkanemay, for example, be cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, cyclooctane, cyclononane and the like,preferably a C₃₋₇ cycloalkane such as cyclopropane, cyclobutane,cyclopentane, cyclohexane and the like. Said cycloalkene may, forexample, be a C₅₋₆ cycloalkene such as cyclopentene, cyclohexene,cyclobutene, cyclopentene and the like. Said cycloalkadiene may, forexample, be a C₅₋₆ cycloalkadiene such as 2,4-cyclopentadiene,2,4-cyclohexadiene, 2,5-cyclohexadiene and the like.

An aryl described above may, for example, be a monocyclic or fusedpolycyclic aromatic hydrocarbon having 6 to 16 carbon atoms, such asbenzene ring, naphthalene ring, anthracene ring, phenanthrene ring,acenaphthalene ring and the like, with a C₆₋₁₀ aryl such as benzene ringand naphthalene ring being especially preferred.

Preferred examples of a cyclic hydrocarbon which may be formed when R¹⁰and R¹¹ are taken together with the adjacent carbon atoms are a C₅₋₇cyclic hydrocarbon, as well as a saturated or unsaturated cyclicaliphatic hydrocarbon (for example, cycloalkane, cycloalkene,cycloalkadiene and the like), especially, cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane andthe like, with a C₃₋₇ cycloalkane such as cyclopropane, cyclobutane,cyclopentane and cyclohexane being particularly preferred.

A substituent which may be possessed by said cyclic hydrocarbon has themeaning similar to the substituent in “an optionally substitutedhydrocarbon group” described above. A substituent on an unsaturatedcyclic aliphatic hydrocarbon described above is preferably an oxo groupor hydroxyl group.

A substituent on an optionally substituted benzene ring and optionallysubstituted pyridine ring represented by ring I and an optionallysubstituted benzene ring and optionally substituted pyridine ringrepresented by ring J in Formula [V] shown above has the meaning similarto the substituent in “an optionally substituted hydrocarbon group”represented by ring A described above.

Ring I is preferably a benzene ring which may be substituted by an alkylgroup, halogenated alkyl group or a halogen atom, with a benzene ringwhich may be substituted by a C₁₋₆ alkyl group, halogenated C₁₋₄ alkylgroup or halogen atom being especially preferred.

Ring J is preferably a benzene ring which may be substituted by ahalogenated alkyl group or a halogen atom, with a benzene ring which maybe substituted by a halogenated C₁₋₄ alkyl group or halogen atom beingespecially preferred.

A preferred example of a compound represented by Formula [I] or a saltthereof is a compound represented by Formula [VI]:

in which each of R¹² and R¹³ is a hydrogen atom, halogen atom oroptionally substituted linear hydrocarbon group, or the both may betaken together with the adjacent carbon atoms to form an optionallysubstituted cyclic hydrocarbon group,

is an optionally substituted phenyl group (preferably, except for2-chlorophenyl ring and 2-fluorophenyl ring), ring L is an optionallysubstituted benzene ring or optionally substituted pyridine ring(preferably, when

is a phenyl group, then R¹³ is not a methyl group, and

is a 2-methylphenyl group, then R¹³ is not a chlorine atom) or a saltthereof.

In Formula [VI] shown above, “an optionally substituted linearhydrocarbon group” represented by R¹² and R¹³ is similar to “anoptionally substituted linear hydrocarbon group” represented by R¹⁰ andR¹¹ described above.

An optionally substituted cyclic hydrocarbon which may be formed whenR¹² and R¹³ are taken together with the adjacent carbon atoms has themeaning similar to “an optionally substituted cyclic hydrocarbon” whichmay be formed when R¹⁰ and R¹¹ are taken together with the adjacentcarbon atoms described above.

Preferred examples of a cyclic hydrocarbon in a cyclic hydrocarbon whichmay be formed when R¹² and R¹³ are taken together with the adjacentcarbon atoms are a C₅₋₇ cyclic hydrocarbon, as well as a saturated orunsaturated cyclic aliphatic hydrocarbon (for example, cycloalkane,cycloalkene, cycloalkadiene and the like), especially, cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane,cyclononane and the like, with a C₃₋₇ cycloalkane such as cyclopropane,cyclobutane, cyclopentane and cyclohexane being particularly preferred.

Each of R¹² and R¹³ is preferably a halogen atom or a C₁₋₃ alkyl group.

In Formula [VI] shown above, “a substituent” on an optionallysubstituted phenyl group represented by Formula:

has the meaning similar to “a substituent” on an optionally substitutedbenzene ring represented by ring I shown above.

A preferred example of

may, for example, be a phenyl group which may be substituted by a C₁₋₃alkyl group.

In Formula [VI] shown above, “an optionally substituted benzene ring andoptionally substituted pyridine ring” represented by ring L has themeaning similar to “an optionally substituted benzene ring andoptionally substituted pyridine ring” represented by ring J shown above.

A preferred example of ring L may, for example, be a substituted benzenering. Such a substituent has the meaning similar to the substituentwhich may be possessed by ring L described above.

A compound represented by Formula [I], [II], [III], [IV], [V] or [VI] ina free form and a pharmacologically acceptable salt thereof areencompassed in the present invention. When a compound represented byFormula [I], [II], [III], [IV], [V] or [VI] has an acidic group such asa carboxyl group, such a salt may be a salt with an inorganic base(e.g., alkaline metals such as sodium and potassium, alkaline earthmetals such as calcium and magnesium, transition metals such as zinc,iron and copper) or an organic base (e.g., organic amines such astrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine andN,N′-dibenzylethylenediamine, basic amino acids such as arginine, lysineand ornithine).

When a compound represented by Formula [I], [II], [III], [IV], [V] or[VI] has a basic group such as an amino group, it may form a salt withan inorganic or organic acid (e.g., hydrochloric acid, nitric acid,sulfuric acid, phosphoric acid, carbonic acid, bicarbonic acid, formicacid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid,oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid,malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like) as well as acidic amino acids suchas aspartic acid, glutamic acid and the like.

A compound represented by Formula [I], [II], [III], [IV], [V] or [VI] ora salt thereof can be employed also as a prodrug. Said prodrug is acompound which is converted into a compound represented by Formula [I],[II], [III], [IV], [V] or [VI] or a salt thereof under a physiologicalcondition in a living body as a result of a reaction with an enzyme orgastric acid, and thus a compound which undergoes an enzymaticoxidation, reduction or hydrolysis to form a compound represented byFormula [I], [II], [III], [IV], [V] or [VI] or a salt thereof and acompound which is hydrolyzed by gastric acid to form a compoundrepresented by Formula [I], [II], [III], [IV], [V] or [VI] or a saltthereof. A prodrug for a compound represented by Formula [I], [II],[III], [IV], [V] or [VI] or a salt thereof may, for example, be acompound obtained by subjecting an amino group in a compound representedby Formula [I], [II], [III], [IV], [V] or [VI] or a salt thereof to anacylation, alkylation or phosphorylation when said compound has an aminogroup (e.g., a compound obtained by subjecting an amino group in acompound represented by Formula [I], [II], [III], [IV], [V] or [VI] or asalt thereof to an eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand t-butylation); a compound obtained by subjecting a hydroxyl group ina compound represented by Formula [I], [II], [III], [IV], [V] or [VI] ora salt thereof to an acylation, alkylation, phosphorylation or borationwhen said compound has a hydroxy group (e.g., a compound obtained bysubjecting the hydroxyl group to an acetylation, palmitoylation,propanoylation, pivaloylation, succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation); a compound obtained by subjecting acarboxyl group in a compound represented by Formula [I], [II], [III],[IV], [V] or [VI] or a salt thereof to an esterification or amidationwhen said compound has a carboxyl group (e.g., a compound obtained bysubjecting the carboxyl group to an ethylesterification,phenylesterification, carboxymethylesterification,dimethylaminoesterification, pivaloyloxymethylesterification,ethoxycarbonyloxyethylesterification, phthalidylesterification,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification,cyclohexyloxycarbonylethylesterification and methylamidation) and thelike. These prodrugs can be produced from a compound represented byFormula [I], [II], [III], [IV], [V] or [VI] or a salt thereof by amethod known per se.

A prodrug for a compound represented by Formula [I], [II], [III], [IV],[V] or [VI] or a salt thereof may also be one which is converted into acompound represented by Formula [I], [II], [III], [IV], [V] or [VI] or asalt thereof under a physiological condition, such as those described in“IYAKUHIN no KAIHATSU (Development of Pharmaceuticals)”, Vol.7, Designof Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990).

A compound represented by Formulae [I], [II], [III], [IV], [V] or [VI]or a salt may be present as a hydrate or anhydride thereof.

A compound represented by Formulae [I], [II], [III], [IV], [V] or [VI]or a salt may be labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S, ¹²⁵I andthe like).

Preferred examples of a compound represented by Formula [I] other thanthose represented by Formulae [II] to [VI] are those disclosed inEPA585913, EPA602598, JP-A-6-263736, JP-A-6-340647, JP-A-8-295667 andWO99-33825.

Among those compounds represented by Formula [I], the followingcompounds:

-   2-[7-Chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide;-   2-[7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;-   2-[7-chloro-4-(3-chloro-4-fluorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide;-   2-[7-chloro-4-(3-chloro-4-fluorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;-   2-[7-chloro-6-methyl-4-(3-methylphenyl)-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide;-   2-[7-chloro-6-methyl-4-(3-methylphenyl)-2-oxo-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;-   2-[7-chloro-2-oxo-4-phenyl-6-[(4-phenylpiperazin-1-yl)methyl]-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide;-   2-[7-chloro-2-oxo-4-phenyl-6-[(4-phenylpiperazin-1-yl)methyl]-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;-   2-[7-chloro-6-[[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl]methyl]-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide;-   2-[7-chloro-6-[[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl]methyl]-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;-   2-[7-chloro-6-[[4-(3-methylphenyl)piperidin-1-yl]methyl]-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide;-   2-[7-chloro-6-[[4-(3-methylphenyl)piperidin-1-yl]methyl]-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;    or a salt thereof are employed preferably.

A compound represented by Formula [I] or a salt thereof encompasses anyknown compounds and novel compounds. Such known compounds [II], [III]and [IV] and their salts are disclosed for example in EPA585913,EPA602598 and JP-A-6-263736 and the like, the disclosure in which arefollowed to produce the compounds. Said novel compounds [V] and [VI] andtheir salts can be produced for example by the following methods. Thus,a compound [I] or a salt thereof can be produced by known methods forproducing Compounds [II], [III] and [IV] described above or by themethods for producing Compounds [V] and [VI] described below, or anyanalogous methods.

A compound [V] or a salt thereof can be produced, as shown below, byreacting a corresponding coumarineacetic acid derivative [VII], or asalt thereof or a derivative thereof which is reactive at its carboxylgroup, with a compound represented by Formula [VIII]:

wherein each symbol is as defined above or a salt thereof. Such areactive derivative of a carboxylic acid-may, for example, be an acidhalide (for example, chloride, bromide and the like), acid anhydride,mixed acid anhydride (for example, anhydride with methyl carbonate,anhydride with ethyl carbonate, anhydride with isobutyl carbonate andthe like), activated ester (for example, ester with hydroxysuccinimide,ester with 1-hydroxybenzotriazole, ester withN-hydroxy-5-norbornene-2,3-dicarboxyimide, ester with p-nitrophenol,ester with 8-oxyquinloine and the like), with an acid halide beingespecially preferred.

A compound [V] or a salt thereof can be produced also by reacting acoumarineacetic acid derivative [VII] or a salt thereof with a compoundrepresented by Formula [VIII] or a salt thereof in the presence of acoupling reagent. Such a coupling reagent may, for example, be acarbodiimide (for example, dicyclohexylcarbodiimide,N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide,N-cyclohexyl-N′-(2-morpholin-4-ylethyl)carbodiimide,N-cyclohexyl-N′-[4-(diethylamimo)cyclohexyl]carbodiimide),carbonyldiimidazole, N-ethyl-5-phenylisoxazolium-3′-sulfonate,N-ethyl-2′-hydroxybenzisoxazolium trifluoroborate,2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline,2-isobutyloxy-1-isobutyloxycarbonyl-1,2-dihydroquinoline,(benzotriazolyl-N-hydroxytrisdiethylaminophosphonium hexafluorophosphidesalt, diphenylphosphoryl azide and the like. In some cases, acarbodiimide can affect the reaction advantageously when combined withadditives. Such additives are N-hydroxysuccinimide,1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine,N-hydrpxy-5-norbornene-2,3-dicarboxylic acid imide, ethyl2-hydroxyimino-2-cyanoacetate, 2-hydroxyimino-2-cyanoacetamide and thelike.

A salt of a compound [VII] is similar to the salt of a compound [I]described above.

This reaction is conducted usually in a solvent by which the reaction isnot affected adversely (for example, a halogenated hydrocarbon such aschloroform, dichloromethane, ethyl ether, tetrahydrofuran, dioxane,dimethoxyethane, ethyl acetate, benzene, toluene, pyridine,N,N-dimethylformamide and the like, ether, ester, hydrocarbon, aromaticamine, amide and the like). This reaction can be conducted in thepresence or absence of a base. The reaction temperature is usually about−10° C. to 120° C., preferably about 0° C. to 100° C. The reaction timeis usually about 5 minutes to 48 hours, preferably about 0.5 to 24hours. The amount of a compound [VIII] or a salt thereof is about 1 to 5molar equivalents, preferably about 1 to 3 molar equivalents, per 1 moleof a compound [VII] or a salt thereof or a reactive derivative thereof.The base may, for example, be an alkylamine such as triethylamine, acyclic amine such as N-methylmorpholine and pyridine, an aromatic aminesuch as N,N-dimethylaniline and N,N-diethylaniline, an alkaline metalcarbonate such as sodium carbonate and potassium carbonate, an alkalinemetal hydrogen carbonate such as sodium hydrogen carbonate and potassiumhydrogen carbonate and the like, and the amount of which is about 1 to 5molar equivalents, preferably about 1 to 3 molar equivalents per 1 moleof a compound [VIII] or a salt thereof. When using a solvent which isimmiscible with water, then a suitable amount of water may be added tothe reaction system to conduct the reaction in a biphasic system. Whenusing a coupling reagent, it is preferable usually to conduct thereaction under an anhydrous condition. The amount of said couplingreagent is about 1 to 10 molar equivalents, preferably about 1 to 3molar equivalents per 1 mole of a compound [VII] or a salt thereof. Whenan additive is employed, the amount is about 1 to 5 molar equivalents,preferably about 1 to 2 molar equivalents per 1 mole of the couplingregent.

A starting compound [VII] or a salt thereof employed in the reactiondescribed above can be obtained for example by the method described inEPA585913 or an analogous method.

A starting compound [VII] or a salt thereof employed in the reactiondescribed above can be obtained also by the methods described below.

wherein R^(c) is an alkyl group (methyl, ethyl, propyl, t-butyl and thelike and other symbols are as defined above.

Reaction step 1 is accomplished by condensing a compound [VII′] or asalt thereof with a reactive derivative of a succinic acid monoester.

A reactive derivative of a succinic acid monoester may, for example, bean acid halide (for example, an acid chloride) of a succinic acidmonoalkylester (e.g., methyl ester, ethyl ester, propyl ester), withethylsuccinicyl chloride being employed preferably. The amount of areactive derivative of a succinic acid monoester employed is usually anequimolar amount to about 10-fold molar amount, preferably an equimolaramount to about 3-fold molar amount, based on a compound [VII′] or asalt thereof. Usually, said reaction is conducted advantageously in thepresence of a base, and such a base is an organic or inorganic base.Such an organic base may, for example, be a tertiary amine (for example,triethylamine, diisopropylethylamine, diazabicycloundecene and thelike). An inorganic base may, for example, be an alkaline metalhydroxide such as lithium hydroxide, sodium hydroxide, potassiumhydroxide and the like; an alkaline metal carbonate such as sodiumcarbonate, potassium carbonate, cesium carbonate and the like; analkaline metal hydrogen carbonate such as sodium hydrogen carbonate,potassium hydrogen carbonate; an alkaline metal hydride such as sodiumhydride and potassium hydride. The amount of a base employed is anequimolar amount to about 10-fold molar amount, preferably an equimolaramount to about 3-fold molar amount, based on a compound [VII′] or asalt thereof.

Said reaction is conducted advantageously in a solvent. Such a solventis a solvent by which the reaction is not affected adversely, includinga hydrocarbon (for example, pentane, hexane, cyclohexane, benzene,toluene and the like), a halogenated hydrocarbon (for example,dichloromethane, chloroform and the like), an ether (for example,diethyl ether, tetrahydrofuran, dioxane and the like), an amide (forexample, N,N-dimethylformamide, hexamethyl phosphoryl triamide and thelike), an urea (for example,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine and the like), anitrile (for example, acetonitrile, propionitrile and the like). Any ofthese solvents can be employed alone or in combination with each otherin a suitable ratio. The amount of a solvent employed is usually about 1to 100 ml, preferably about 10 to 50 ml per 1 g of a compound [VII′] ora salt thereof. The reaction temperature is usually about −20° C. to theboiling temperature of the solvent employed for the reaction, preferablyabout 25° C. to 100° C.

The reaction time may vary depending on the types of the base and thereaction solvent employed and the reaction temperature, it is about 10minutes to 24 hours, preferably about 20 minutes to 12 hours.

Reaction step 2 is accomplished by treating a compound [VII″] with abase. Said base may, for example, be those exemplified in Reaction step1, and the amount of a base employed is usually about 0.1-fold molaramount to 10-fold molar amount, preferably about 0.1-fold molar amountto 1-fold molar amount based on a compound [VII″] or a salt thereof.

Said reaction is conducted advantageously in a solvent. Such a solventis a solvent by which the reaction is not affected adversely, includinga hydrocarbon (for example, pentane, hexane, cyclohexane, benzene,toluene and the like), a halogenated hydrocarbon (for example,dichloromethane, chloroform and the like), an ether (for example,diethyl ether, tetrahydrofuran, dioxane and the like), an amide (forexample, N,N-dimethylformamide, hexamethyl phosphoryl triamide and thelike), an urea (for example,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine and the like), anitrile (for example, acetonitrile, propionitrile and the like). Any ofthese solvent can be employed alone or in combination with each other ina suitable ratio. The amount of a solvent employed is usually about 1 to100 ml, preferably about 10 to 50 ml per 1 g of a compound [VII′] or asalt thereof. The reaction temperature is usually about 20° C. to theboiling temperature of the solvent employed for the reaction, preferablyabout 25° C. to 120° C.

The reaction time may vary depending on the types of the base and thereaction solvent employed and the reaction temperature, it is about 30minutes to 24 hours, preferably about 1 hour to 12 hours.

Said reaction may sometimes be accomplished advantageously by removingwater generated during the reaction for example by using a Dien-Starkazeotropic dehydration device.

It is also possible that the reaction step 1 and the reaction step 2 canbe accomplished in one pot. For example, by using as a reactivederivative of a succinic acid monoester an acid halide (e.g., acidchloride and the like) of a succinic acid monoalkyl ester (e.g., methylester, ethyl ester, propyl ester) and as a base a tertiary amine (forexample, triethylamine, diisopropylethylamine, diazabicycloundecene andthe like) in excess, a compound [VII″′] or a salt can be produced all atonce from a compound [VII″] or a salt thereof. The amount of an acidhalide employed in such a case is usually about 1.5-fold molar amount to10-fold molar amount, preferably about 1.5-fold molar amount to 3-foldamount based on a compound [VII″] or a salt thereof. The amount of abase employed is usually about 2-fold molar amount to 10-fold molaramount, preferably about 2-fold molar amount to 5-fold amount based on acompound [VII″] or a salt thereof.

Said reaction is conducted advantageously in a solvent. Such a solventis a solvent by which the reaction is not affected adversely, and thetype and the amount of a solvent employed are similar to those thereaction step 1. The reaction temperature is usually about 20° C. to theboiling temperature of the solvent employed for the reaction, preferablyabout 25° C. to 60° C. The reaction time may vary depending on the typesof the acid halide and the base, the type of the reaction solvent andthe reaction temperature, it is about 30 minutes to 24 hours, preferablyabout 30 minutes to 4 hours.

Reaction step 3 is accomplished by treating a compound [VII″′] with anacid or base.

Such an acid may, for example, be an organic acid (for example, formicacid, acetic acid, trichloroacetic acid, trifluoroacetic acid,benzensulfonic acid, p-toluensulfonic acid and the like), or aninorganic acid (for example, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid and the like), any of whichmay be employed alone or in combination with each other in a suitableratio. Said base may, for example, be an alkaline metal hydroxide (forexample, lithium hydroxide, sodium hydroxide, potassium hydroxide andthe like), an alkaline metal carbonate (For example, sodium carbonate,potassium carbonate, cesium carbonate and the like), an alkaline metalhydrogen carbonate (for example, sodium hydrogen carbonate, potassiumhydrogen carbonate and the like). The amount of an acid or base employedis usually about 1 molar amount to 100-fold molar amount, preferablyabout 1 molar amount to 10-fold molar amount based on a compound[VII″′].

Said reaction is conducted advantageously in a solvent. Such a solventis a solvent by which the reaction is not affected adversely, includinga hydrocarbon (for example, pentane, hexane, cyclohexane, benzene andthe like), a lower alcohol (for example, methanol, ethanol, propanol andthe like), an ether (for example, diethyl ether, tetrahydrofuran,dioxane and the like), an amide (for example, N,N-dimethylformamide,hexamethyl phosphoryl triamide and the like), an urea (for example,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine and the like). In areaction using an acid, an acid described above can be employed as asolvent. Any of these solvent can be employed alone or in combinationwith each other in a suitable ratio, or in combination with water. Theamount of a solvent employed is usually about 1 to 100 ml, preferablyabout 10 to 50 ml per 1 g of a compound [VII″′] or a salt thereof. Thereaction temperature is usually about −20° C. to the boiling temperatureof the solvent employed for the reaction, preferably about 15° C. to120° C. The reaction time may vary depending on the types of the acidand the reaction solvent employed and the reaction temperature, it isabout 10 minutes to 24 hours, preferably about 30 minutes to 12 hours.

Furthermore, a coumarinamide condensed with a cycloalkane which has oxogroup can be synthesized also by subjecting a coumarinamide condensedwith a cycloalkane to an oxidation reaction at an appropriate stage ofthe synthesis. Such an oxidation reaction can be accomplished using anoxidant (for example, permanganate, chromate and the like) by a methodknown per se [for example, A. B. Smith, III, et. al., The Journal ofOrganic Chemistry, Vol.50, p3239-3241, 1985).

Salts of the compounds [VII′], [VII″] and [VII″′] employed in thereactions described above are similar to those salts of a compound [I]described above.

A compound [VI] or a salt thereof can be produced by, for example, thefollowing method [1] or [2] shown below.

wherein each symbol is as defined above.

The reaction of a carboxylic acid represented by Formula [IX] or a saltthereof or a reactive derivative thereof with a compound represented byFormula [X] or a salt thereof is an amide bond- or urea bond-formingreaction, which can be accomplished by various known method. Forexample, when reacting a compound [IX] or a salt thereof (for example, asalt with an alkaline metal such as sodium, potassium, magnesium and thelike, alkaline earth metal and the like) with a compound [X] or a saltthereof (for example, a salt with an inorganic acid such as hydrochloricacid, sulfuric acid and the like, a salt with an organic acid such asmethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalicacid, fumaric acid, maleic acid and the like), it is preferable usuallythat an appropriate condensing agent is employed or that such a compound[IX] or a salt thereof is once derivatized to its reactive derivativeand subsequently reacted with a compound [X] or a salt thereof. Such acondensing agent may, for example, be dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, diethylcyanophosphate, diphenylphosphoryl azide and the like. When using such acondensing agent, the reaction can be conducted advantageously in asolvent by which the reaction is not affected adversely (for example,ethers, esters, halogenated hydrocarbons, hydrocarbons, amides,sulfoxides such as tetrahydofuran, dioxane, dimethoxyethane, ethylacetate, dichloromethane, 1,2-dichloroethane, benzene, toluene,N,N-dimethylformamide, dimethylsulfoxide and the like). This reactioncan be promoted in the presence of a base, and the reaction is conductedat a temperature of about −10° C. to 100° C., preferably about 0° C. to60° C. The reaction time is usually about 1 to 96 hours, preferablyabout 1 to 72 hours. The amounts of a compound [IX] or a salt thereofand a condensing agent employed are about 1 to 5 molar equivalents,preferably about 1 to 3 molar equivalents per 1 mole of a compound [X]or a salt thereof. A base employed may, for example, be an alkylaminesuch as triethylamine, cyclic amine such as N-methylmorpholine andpyridine, and the amount employed is about 1 to 5 molar equivalents,preferably about 1 to 3 molar equivalents per 1 mole of a compound [IX]or a salt thereof.

A reactive derivative of a compound [IX] may, for example, be an acidhalide (for example, chloride, bromide and the like), acid anhydride,mixed acid anhydride (for example, anhydride with methyl carbonate,anhydride with ethyl carbonate, anhydride with isobutyl carbonate andthe like), activated ester (for example, ester with hydroxysuccinimide,ester with 1-hydroxybenzotriazole, ester withN-hydroxy-5-norbornene-2,3-dicarboxyimide, ester with p-nitrophenol,ester with 8-oxyquinloine and the like). The reaction between a compound[IX] or a salt thereof and a reactive derivative of a compound [X] isconducted usually in a solvent (for example, halogenated hydrocarbons,ethers, esters, hydrocarbons and amides such as chloroform,dichloromethane, 1,2-dichloroethane, ethyl ether, tetrahydrofuran,dioxane, dimethoxyethane, ethyl acetate, benzene, toluene, pyridine,N,N-dimethylformamide and the like). This reaction can be promoted inthe presence of a base. The reaction is conducted at a temperature ofabout −10° C. to 120° C., preferably about 0° C. to 100° C. The reactiontime is usually about 0.5 to 48 hours, preferably about 1 to 24 hours.The amount of a compound [X] or a salt thereof employed is about 1 to 5molar equivalents, preferably about 1 to 3 molar equivalents per 1 moleof a reactive derivative of a compound [IX]. A base employed may, forexample, be an alkylamine such as triethylamine, a cyclic amine such asN-methylmorpholine and pyridine, an aromatic amine such asN,N-dimethylaniline and N,N-diethylaniline, an alkaline metal carbonatesuch as sodium carbonate and potassium carbonate, an alkaline metalhydrogen carbonate such as sodium hydrogen carbonate and potassiumhydrogen carbonate, and the amount employed is about 1 to 5 molarequivalents, preferably about 1 to 3 molar equivalents per 1 mole of acompound [IX] or a reactive derivative thereof. When using a solventwhich is immiscible with water in this reaction, water may be added in asuitable ratio to the reaction system to perform the reaction in abiphasic system.

wherein each symbol is as defined above.

This method is a method for forming a urea derivative by reacting anamine derivative compound [XI] or a salt thereof (e.g., salt with amineral acid such as hydrochloric acid, sulfuric acid and the like, asalt with an organic acid such as methanesulfonic acid, benzenesulfonicacid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid andthe like) with an isocyanate derivative compound [XII]. In this method,a reaction using such an isocyanate form [XII] and a compound [XI] or asalt thereof yields an urea derivative. While this reaction can beconducted without using any solvent, it is effective to conduct thereaction in a solvent. Such a solvent may be any solvent provided thatit does not interfere with the reaction, and is preferably an ether(e.g., diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane and the like), an aromatic hydrocarbon (e.g., benzene,toluene, xylene and the like), an ester (e.g., methyl acetate, ethylacetate and the like), an amide (e.g., N,N-dimethylformamide and thelike), a sulfoxide (e.g., dimethyl sulfoxide and the like). When using acompound [XII] in a form of a salt, the reaction can be accomplishedadvantageously by adding a desalting agent if desired. Such a desaltingagent may, for example, be a tertiary amine such as trimethylamine,triethylamine, N-methylmorpholine and the like, and an aromatic aminesuch as pyridine, picoline and N,N-dimethylaniline. The amount of such adesalting agent employed is about 1 to 5 molar equivalents, preferablyabout 1 to 3 molar equivalents per 1 mole of a salt of a compound [XII].The reaction temperature is usually about −10° C. to 180° C., preferablyabout 0° C. to 120° C. The reaction time is usually about 15 minutes to40 hours, preferably about 30 minutes to 20 hours. The amount of acompound [XII] or a salt thereof employed is about 1 to 5 molarequivalents, preferably about 1 to 3 molar equivalents per 1 mole of acompound [XI] or a salt thereof.

A starting compound [IX], [XI] or a salt thereof employed in thereaction described above can be obtained for example by the methoddescribed in EPA602598 or an analogous method.

In each reaction for producing a compound [V], [VI] or a salt thereofdescribed above and each reaction for synthesizing a starting compound,a starting compound having an amino group, carboxy group or hydroxygroup as its substituent may be present as a compound in which aprotective group employed ordinarily in a peptide chemistry has beenintroduced into such a substituent, and an intended compound can beobtained by deprotection if necessary after the reaction.

A protective group for an amino group may, for example, be a formyl oreach optionally substituted C₁₋₆ alkyl-carbonyl (for example, acetyl,ethylcarbonyl and the like), phenylcarbonyl, C₁₋₆ alkyl-oxycarbonyl (forexample, methoxycarbonyl, ethoxycarbonyl and the like),phenyloxycarbonyl, C₇₋₁₀ aralkyl-carbonyl (for example, benzylcarbonyl),trityl, phthaloyl, N,N-dimethylaminomethylene and the like. Itssubstituent may, for example, be a halogen atom (for example, fluorine,chlorine, bromine, iodine), C₁₋₆ alkyl-carbonyl (for example,methylcarbonyl, ethylcarbonyl, butylcarbonyl and the like), nitro andthe like, and the number of the substituents may be 1 to 3.

A protective group for a carboxy may, for example, be each optionallysubstituted C₁₋₆ alkyl (for example, methyl, ethyl, n-propyl, i-propyl,n-butyl, tert-butyl and the like), phenyl, trityl, silyl and the like.Its substituent -may, for example, be a halogen atom (for example,fluorine, chlorine, bromine, iodine), formyl, C₁₋₆ alkyl-carbonyl (forexample, acetyl, ethylcarbonyl, butylcarbonyl and the like), nitro groupand the like, and the number of the substituents may be 1 to 3.

A protective group for a hydroxy may, for example, be each optionallysubstituted C₁₋₆ alkyl (for example, methyl, ethyl, n-propyl, i-propyl,n-butyl, tert-butyl and the like), phenyl, C₇₋₁₀ aralkyl (for example,benzyl and the like), formyl, C₁₋₆ alkyl-carbonyl (for example, acetyl,ethylcarbonyl and the like), phenyloxycarbonyl, benzoyl, C₇₋₁₀aralkyl-carbonyl (for example, benzylcarbonyl), pyranyl, furanyl, silyland the like. Its substituent may, for example, be a halogen atom (forexample, fluorine, chlorine, bromine, iodine and the like), C₁₋₆ alkyl(for example, methyl, ethyl, n-propyl), phenyl, C₇₋₁₀ aralkyl (forexample, benzyl and the like), nitro and the like, and the number of thesubstituents may be 1 to 4.

A deprotection method may be a method known per se on an analogousmethod, for example, a treatment with an acid, base, reduction, UV,hydrazine, phenylhydrazine, sodium N-methyldichiocarbamate,tetrabutylammonium fluoride, palladium acetate and the like.

A compound [V], [VI] or a salt thereof obtained by a method describedabove can be isolated and purified by an ordinary separation means suchas recrystallization, distillation and chromatography. When an inventivecompound [V] or [VI] thus obtained is in a free form, it can beconverted into a salt by a method known per se or an analogous method(for example, neutralization), while a compound [V] or [VI] which isobtained in the form of a salt can be converted into a free form oranother salt by a method known per se or an analogous method.

Since each of inventive compounds [I], [II], [III], [IV], [V], [VI] andtheir salts and prodrug (hereinafter abbreviated as inventive compounds)has a low toxicity and also is safe while having a lipid-rich plaqueregressing effect, it can be employed as a prophylactic or therapeuticagent in mammals (for example, mouse, rat, rabbit, dog, cat, cattle,pig, monkey, human and the like) against acute coronary artery syndromesuch as acute myocardial infarction, unstable angina and the like,peripheral artery occlusion, restenosis after percutaneous transluminalcoronary angioplasty (PTCA), ischemic heart disease such as myocardialinfarction and angina pectoris, arteriosclerosis, intermittentclaudication, apoplexy (cerebral infarction, cerebral embolism, cerebralhemorrhage and the like), lacunar infarction, cerebrovascular dementia,and is useful as a plaque regressing agent.

Each of novel compounds [V], [VI] and their salts has an ACAT inhibitingeffect (preferably macrophage ACAT inhibiting effect, ACAT of subtype 1inhibiting effect) similarly to known compounds [I], [II], [III], [IV]and their salts, and has a low toxicity similarly to [I], [II], [III],[IV] and their salt, and each of the novel compounds [V], [VI] and theirsalts and prodrug can be employed as a safe prophylactic or therapeuticagent in mammals (for example, mouse, rat, rabbit, dog, cat, cattle,pig, monkey, human and the like) against hypercholesteremia,atherosclerosis and diseases caused thereby (for example, ischemic heartdisease such as myocardial infarction, cerebrovascular impairment suchas cerebral infarction and apoplexy) similarly to known compounds [I],[II], [III], [IV] and their salts and prodrug.

Also according to the invention, an arteriosclerotic focus progressioninhibitor comprising a compound having a lipid-rich plaque regressingeffect or a salt thereof (preferably a compound of the presentinvention) is provided, and such an progression inhibitor is employedpreferably in combination with an HMG-CoA reductase inhibitor.

In the treatment of each of the diseases listed above, a compound of thepresent invention may be employed alone in the treatment, or may becombined with other pharmaceutical components such as otherhypolipidemic agent or hypocholesteremic agent, myocardial protectingagent, coronary artery disease treating agent, diabetes treating agent,thyroid dysfunction treating agent, nephrotic syndrome treating agent,osteoporosis treating agent or chronic renal failure treating agent, andin such a case it is preferable that each of these compounds isadministered in an oral formulation, or in a suppository as a rectalformulation if desired. In such a case, a possible compound to becombined may, for example, be a fibrate [for example, clofibrate,bezafibrate, gemfibrosil and the like], nicotinic acid, derivatives andanalogues thereof [e.g., acipimox and probcol], bile acid-binding resin[e.g., cholestylamine, cholestipol and the like], cholesterol absorptioninhibiting compound [e.g., sitosterol, neomycin and the like],cholesterol biosynthesis inhibiting compound [e.g., an HMG-COA reductaseinhibitor such as lovastatin, simvastatin, pravastatin and the like],squalene epoxidase inhibiting agent [e.g., NB-598 and analogues and thelike].

Still other components to be combined are oxidesqualene-lanosterolcyclase, such as a decalin derivative, azadecalin derivative and indanederivative.

Also when combining with:

Diabetes treating agent [actos, lodiglitazon, kinedak, penfill, humalin,euglucon, glimicron, daonil, novolin, monotard, insulins, glucobay,dimelin, rastinon, bacilcon, deamelin S, Iszilins]; hypothyroidismtreating agent [dried thyroid gland (thyreoid), levothyroxine sodium(thyradin S), liothyronidin sodium (thyronine, thyromin);

Nephrotic syndrome treating agent: prednisolone (Predonine),prednisolone succinate sodium (Predonine), methylprednisolone succinatesodium (Solu medrol), betamethasone (rinderon)]; anticoagulating agent[dipyridamole (Persantin), dilazep hydrochloride (comelian),ticlopidine, clopidogrel, Xa inhibitor]; chronic renal failure treatingagent [diuretics [e.g., furosemide (lasix), bumetamide (lunetron),azosemide (diart)], hypotensive agent (e.g., ACE inhibitor, (enalaprilmaleate (renivase)) and Ca antagonist (manidipine), α-receptor blocker,AII antagonist (candesartan)]; an oral administraiton is preferred.

In view of the lipid-rich plaque regressing effect, the compound of thepresent invention is suitable for preventing and treating a thrombusformation. For this purpose, it is employed alone or in combinaiton witha known therapeutic agent listed below and administred preferably via anoral route.

Thrombus formation preventing agent: anticoagulating agent [e.g.,heparin sodium, heparin potassium, warfarin potasium (warfarin), Xainhibitor], thrombolytic agent [e.g., tPA, urokinase], antiplateletagent [e.g., asprin, sulfinpyrazone (anturan), dipyridamole (persantin),ticlopidine (panaldine), cilostazol (pletal), GPIIb/IIIa antagonist(ReoPro)]; Coronary vasodilating agent: nifedipine, diltiazem,nicorandil, nitrous acid agent; Myocardial protecting agent: CardiacATP-K antagonist, endoserine antagonist, urotensin antagonist and thelike. An inventive compound can be given orally or parenterally, byinjection, infusion, inhalation, rectal administration, or topicaladministration, and can be used as it is or in a pharmaceuticalformulation (for example, powder, granule, tablet, pill, capsule,injection, syrup, emulsion, elixir, suspension, solution and the like).Thus, at least one inventive compound can be employed alone or in amixture with a pharmaceutically acceptable carrier (adjuvant, excipient,auxiliary agent and/or diluent and the like).

A pharmaceutical composition can be formulated in accordance with anordinary method. Such a formulation can be produced usually bymixing/kneading an active component with additives such as an excipient,diluent and carrier. In this specification, a parenteral administrationmeans to include subcutaneous injection, intravenous injection,intramuscular injection, intraperitoneal injection or dripping infusionand the like. A formulation for injection such as aseptic aqueoussuspension or oily suspension for injection can be produced using asuitable dispersing agent or wetting agent and a suspending agent by amethod known in the art. Such an aseptic formulation for injection maybe an aseptic injectable solution or suspension in a diluent or solventwhich can be non-toxic and administered parenterally, including anaqueous solution. An acceptable vehicle or solvent which can be employedmay, for example, be water, Ringer's solution, isotonic saline and thelike. An aseptic non-volatile oil can also be used usually as a solventor suspending medium. For such purpose, any non-volatile oil or fattyacid can be employed, including naturally occurring or synthetic orsemi-synthetic fatty oil or fatty acid, as well as naturally occurringor synthetic or semi-synthetic mono- or di- or tri-glycerides.

A suppository for rectal administration can be produced by mixing anactive ingredient with a suitable non-irritating excipient which issolid at ambient temperature but becomes liquid at the temperature in anintestinal tract to melt in rectum whereby releasing the activeingredient, such as cocoa butter and polyethylene glycols.

A suitable base (e.g. polymer of butyric acid, polymer of glycolic acid,copolymer of butyric acid and glycolic acid, mixture of a polymer ofbutyric acid and a polymer of glycolic acid, polyglycerol fatty acidester and the like) may be combined to form a sustained releaseformulation.

A solid dosage form for oral administration may, for example, be apowder, granule, tablet, pill, capsule and the like, as described above.The formulation of such a dosage form can be produced by mixing and/orkneading an active compound with at least one of the additives, such assucrose, milk sugar (lactose), cellulosic saccharide, mannitol(D-mannitol), maltitol, dextran, starches (e.g., corn starch),microcrystalline cellulose, agar, alginates, chitins, chitosans,pectins, tragacanth gums, gum arabic, gelatins, collagens, casein,albumin, synthetic or semi-synthetic polymers or glycerides. Such adosage form can further contain additives as usual, including inertdiluents, lubricants such as magnesium stearate, preservatives such asparabens and sorbic acid, antioxidants such as ascorbic acid,α-tocopherol and cysteine, disintegrants (e.g., croscarmellose sodium),binder (e.g., hydroxypropyl cellulose), thickening agents, bufferingagents, sweeteners, flavoring agents, perfumes and the like. A tabletand pill may further be enteric-coated. An oral liquid formulation may,for example, be a pharmaceutically acceptable emulsion, syrup, elixir,suspension, solution and the like, which may contain a pharmaceuticallycustomary inert diluent such as water and if desired, additives. Such anoral liquid formulation can be produced by mixing an active ingredient,inert diluent and other additives if necessary in accordance with acustomary method. An oral formulation usually contain about 0.01 to 99%by weight, preferably about 0.1 to 90% by weight, usually about 0.5 to50% by weight of an inventive active compound, although the amount mayvary depending on the dosage form.

The dose in a certain patient is determined considering the age, bodyweight, general condition, sex, diet, administraiton time,administraiton mode, excretion rate, drug combination, degree of thedisease treated currently as well as other factors.

A lipid-rich plaque regressing agent containing a compound of thepresent invention has a low toxicity and can be used safely, and itsdaily dose varies depending on the condition and body weight of thepatient, the type of the compound and the administration route and, forexample, when used as a prophylactic and therapeutic agent againsthyperlipidemia, it may be about 1 to 500 mg, preferably about 10 to 200mg as an active ingredient [I] in an oral formulation, and about 0.1 to100 mg, preferably about 1 to 50 mg, usually about 1 to 20 mg as anactive ingredient [I] in a parenteral formulation for an adult (60 kg),a dose within which exhibited no toxicity.

The present invention also provides:

-   (1) a pharmaceutical composition comprising a compound of the    present invention with a concomitant drug (hereinafter referred to    as a concomitant formulation),-   (2) a method for regressing a lipid-rich plaque which comprises    administering a combination of an effective amount of a compound of    the present invention and an effective amount of a concomitant drug    to a mammal, and,-   (3) a method for preventing and treating acute coronary artery    syndrome such as acute myocardial infarction and unstable angina,    peripheral artery occlusion, restenosis after percutaneous    transluminal coronary angioplasty (PTCA), hypercholesteremia,    atherosclerosis, ischemic heart disease such as myocardial    infarction, cerebrovascular impairment such as cerebral infarction    and apoplexy by administering a combination of an effective amount    of a compound of the present invention and an effective amount of a    concomitant drug to a mammal.

A concomitant drug which can be used in combination with a compound ofthe present invention may, for example, be the pharmaceutical componentsother than the inventive compounds described above and otherhyperlipidemia treating agents, diuretics, hypertension treating agents,cardiac failure treating agents, arrhythmia treating agents,anticoagulants, antiplatelet agents, diabetes treating agents, HDLincreasing agents, unstable plaque stabilizing agents, vasodilators,vasoconstrictors, hypertensive agents, antibacterial agents, antifungalagents, non-steroidal antiinflammatory agents, steroidal agents,immunoregulating agents, antiprotozoal agents, anti-ulcer agents,bronchospasmolytic expectorants, sedatives, narcotics, anxiolyticagents, antipsychotic agents, muscle relaxants, antiepileptic agents,antidepressants, narcotic antagonists, anti-tumor agents, anti-allergicagents, vitamins, vitamin derivatives, bone-calcium metabolizing agents,osteoporosis treating agents, arthritis treating agents, antirheumaticagents, anti-asthmatic agents, pollakiuria/incontinence treating agents,renal failure/nephrosis treating agents, atopic dermatitis treatingagents, allergic rhinitis treating agents, endotoxin antagonists orantibodies, signal transmission inhibitors, inflammatory mediatingeffect inhibitors, inflammatory mediating effect inhibiting antibodies,anti-inflammatory mediating effect inhibitors, anti-inflammatorymediating effect inhibiting antibodies and the like, with hyperlipidemiatreating agents, diuretics, hypertension treating agents, cardiacfailure treating agents, arrhythmia treating agents, anticoagulants,antiplatelet agents, diabetes treating agents, HDL increasing agents,unstable plaque stabilizing agents being preferred. Concomitant drugsother than those described above are specifically those listed below.

(1) Hyperlipidemia Treating Agents

HMG-CoA reductase inhibitors (e.g., fluvastatin, cerivastatin,atorvastatin and the like), fibrates (e.g., simfibrate, clofibratealuminium, clinofibrate, fenofibrate and the like), anion exchangeresins (e.g., cholestyramide and the like), nicotinic acid formulations(e.g., nicomol, niceritrol, tocopherol nicotinate and the like),polyvalent unsaturated fatty acid derivatives (e.g., ethyl icosapentate,polyene phosphatidylcholine, melinamide and the like), vegetable sterols(e.g., γ-oryzanol, soysterol and the like), elastases, sodium dextransulfate, squalene synthetase inhibitor, CETP inhibitor, ethyl2-chloro-3-[4-(2-methyl-2-phenylpropoxy)phenyl]propionate [Chem. Pharm.Bull., 38, 2792, 2796 (1990)] and the like.

(2) Diuretics

Thiazide diuretics (benzylhydro-chlorothiazide, cyclopenthiazide,ethiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide,penfluthiazide, polythiazide, trichloromethiazide and the like), loopdiuretics (clortharidone, clofenamide, indapamide, mefruside, meticrane,sotolazone, tripamide, quinethazone, metolazone, furosemide, mefrusideand the like), potassium retaining diuretics (spironolacton, triamtereneand the like).

(3) Hypertension Treating Agents

[1] Sympathetic Nerve Suppressants

α₂ stimulants (e.g., clonidine, guanabenz, guanfacine, methyldopa andthe like), ganglionic blocking agents (e.g., hexamethonium, trimethaphanand the like), presynaptic blockers (e.g., alseroxylon,dimethylaminoreserpinate, rescinamine, reserpine, syrosingopine and thelike), neuron blockers (e.g., betanidine, guanethidine and the like), α₁blockers (e.g., bunazosin, doxazocin, prazosin, terazosin, urapidil andthe like), β blockers (e.g., propranolol, nadolol, timolol, nipradilol,bunitrolol, indenolol, penbutolol, carteolol, carvedilol, pindolol,acebutolol, atenolol, bisoprolol, metoprolol, labetalol, amosulalol,arotinolol and the like).

[2] Vasodilators

Calcium channel antagonists (e.g., manidipine, nicardipine, nilvadipine,nisoldipine, nitrendipine, benidipine, amlodipine, aranidipine and thelike), phthalazine derivatives (e.g., budralazine, cadralazine,ecarazine, hydralazine, todralazine and the like) and the like.

[3] ACE Inhibitors

Alacepril, captopril, cilazapril, delapril, enalapril, lisinopril,temocapril, trandolapril, quinapril, imidapril, benazepril, perindopriland the like.

[4] AII Antagonists

Losartan, candesartan, valsartan, telimisartan, irbesartan, forasartanand the like.

[5] Diuretics (for Example, Diuretics Described Above)

(4) Cardiac Failure Treating Agents

Cardiotonic agents (e.g., digitoxin, digoxin, methyldigoxin, lanatosideC, proscillaridine and the like), α,β-stimulants (e.g., epinephrine,norepinephrine, isoproterenol, dopamine, docarpamine, dobutamine,denopamine and the like), phosphodiesterase inhibitors (e.g., aminone,milrinone, olprinone hydrochloride and the like), calcium channelsensitivity promoters (e.g., pimobendan and the like), nitrate agents(e.g., nitroglycerin, isosorbide nitrate and the like), ACE inhibitors(for example, ACE inhibitors described above), diuretics (for example,diuretics described above), carperitide, ubidecarenone, vesnarinone,aminophylline and the like.

(5) Arrhythmia Treating Agents

Sodium channel blockers (e.g., quinidine, procainamide, disopyramide,ajimaline, cibenzoline, lidocaine, diphenyl hydantoin, mexiletine,propafenone, flecainide, pilsicainide, phenytoin and the like),β-blockers (e.g., propranolol, alprenolol, bufetolol, oxprenolol,atenolol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol,arotinolol and the like), potassium channel blockers (e.g., amiodaroneand the like), calcium channel blockers (e.g., verapamil, diltiazem andthe like) and the like.

(6) Anticoagulants and Antiplatelet Agents

Sodium citrate, activated protein C, tissue factor pathway inhibitors,anti-thrombin III, dalteparin sodium, argatroban, gabexate, sodiumozagrel, ethyl icosapentate, beraprost sodium, alprostadil,pentoxifylline, tisokinase, streptokinase and the like.

(7) Diabetes Treating Agents

Sulfonyl ureas (e.g., tolbutamide, chlorpropamide, glyclopyramide,acetohexamid, tolazamide, glibenclamide, glybuzole and the like),biguamides (e.g., metformin hydrochloride, buformin hydrochloride andthe like), α-glucosidaseinhibitor (e.g., voglibose, acarbose and thelike), insulin sensitizer (e.g., pioglitazone, troglitazone and thelike), insulin, glucagon, diabetic complication treating agent (e.g.,epalrestat and the like) and the like.

(8) HDL Increasing Agents

Squalene synthetase inhibitors, CETP inhibitors, LPL activators and thelike.

(9) Unstable Plaque Stabilizing Agents

MMP inhibitors, kinase inhibitors.

(10) Vasodilators

Oxyphedrine, diltiazem, tolazoline, hexobendine, bamethan, clonidine,methyldopa, guanabenz and the like.

(11) Vasoconstrictors

Dopamine, dobutamine denopamine and the like.

(12) Hypertensive Agents

Dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin,lanatoside C, G-Strophantin and the like.

(13) Antibacterial Agents

[1] Sufonamides

Sulfamethizole, sulfisoxazole, sulfamonomethoxin, sulfamethizole,salazosulfapyridine, silver sulfadiazine and the like.

[2] Quinolones

Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin,ofloxacin, tosufloxacin tosilate, ciprofloxacin hydrochloride,lomefloxacin hydrochloride, sparfloxacin, fleroxacin and the like.

[3] Anti-Tuberculous Agents

Isoniazid, ethambutol(ethambutol hydrochloride), p-aminosalicylic acid(calcium p-aminosalicylate), pyrazinamide, ethionamide, prothionamide,rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and thelike.

[4] Anti Acid-Fast Bacteria Agents

Diaphenylsulfone, rifampicin and the like.

[5] Anti-Viral Agents

Idoxuridine, acyclovir, vidarabine, ganciclovir and the like.

[6] Anti-HIV Agent

Zidovudine, didanosine, zalcitabine, indinavir sulfate ethanol adduct,ritonavir and the like.

[7] Anti-Spirochete Agents

[8] Antibiotics

Tetracyclin hydrochloride, ampicillin, piperacillin, gentamycin,dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin,sisomicin, tetracyclin, oxytetracyclin, rolitetracyclin, doxycyclin,ampicillin, piperacillin, ticarcillin, cefalotin, cefapirin,cefaloridine, cefaclor, cefalexin, cefroxadine, cefadroxil, cefamandole,cefotoam, cefroxime, cefotiam, cefotiam hexetil, cefuroxime axetil,cefdinir, cefditoren pivoxil, ceftazidime, cefpiramide, cefsulodin,cefinenoxime, cefpodoxime proxetil, cefpirome, cefozopran, cefepime,cefsulodin, cefinenoxime, cefinetazole, cefminox, cefoxitin,cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime, cefoperazon,ceftizoxime, moxalactam, thienamycin, sulfazecin, azthreonam and theirsalts, griseofulvin, lankacidin [J. Antibiotics, 38, 877-885 (1985)] andthe like.

(14) Antifungal Agents

-   [1] Polyene-based antibiotics (e.g., amphotericin B, nystatin,    trichomycin).-   [2] Griseofulvin, pyrrolnitrin and the like.-   [3] Cytosine metabilism antagonists (e.g., flucytosine).-   [4] Imidazole derivatives (e.g., econazole, clotrimazole, miconazole    nitrate, bifonazole, croconazole).-   [5] Triazole derivatives (e.g., fluconazole, itraconazole,    azole-based compound [2-[(1R,    2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl-3-(2H,4H)-1,2,4-triazolone).-   [6] Thiocarbamic acid derivatives (e.g., trinaphthol).-   [7] Echinocandin-based derivatives (e.g., caspofamgine, FK-463,    V-Echinocadin) and the like.-   (15) Non-steroidal antiinflammatory agents

Acetaminophen, fenasetin, ethenzamide, sulpyrine, antipyrine, migrenin,aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofensodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen,oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine, epirizol,tiaramide hydrochloride, zaltoprofen, gabexate mesilate, camostatmesilate, ulinastatin, colchicine, probenecid, sulfinpyrazone,benzbromarone, allopurinol, sodium gold thiomalate, sodium hyaluronate,sodium salicylate, morphine hydrochloride, salicylic acid, atropine,scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen,oxymorphone and their salts.

(16) Steroidal Agents

Dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone,triamcinolone acetonide, fluorocinonide, fluorocinolone acetonide,prednisolone, methylprednisolone, cortisone acetate, hydrocortisone,fluorometholone, beclometasone dipropionate, estriol and the like.

(17) Immunoregulating Agents

Cyclosporin, tacrolimus, gusperimus, azathioprine, anti-lymph serum,dried sulfonated immunogloburin, erythropoietin, colony stimulatingfactor, interleukin, interferon and the like.

(18) Antiprotozoal Agents

Metronidazole, timidazole, diethylcarbamadine citrate, quininehydrochloride, quinine sulfate and the like.

(19) Anti-ulcer Agents

Metoclopramide, histidine hydrochloride, lansoprazole, metoclopramide,pirenzepine, cimetidine, ranitidine, famotidine, urogastrine,oxethazaine, proglumide, omeprazole, sucralfate, sulpiride, cetraxate,gefarnate, aldioxa, teprenone, prostaglandin and the like.

(20) Bronchospasmolytic Expectorants

Ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate,dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrinehydrochloride, methylephedrine hydrochloride, noscapine hydrochloride,aroclamide, chlorfesianol, picoperidamine, cloperastine, protokylol,isoproterenol, sulbutamol, terbutaline, oxymetebanol, morphinehydrochloride, dextromethorphan hydrobromide, oxycodone hydrochloride,dimemorfan phosphate, tipepidine hibenzate, pentoxyverine citrate,clofedanol hydrochloride, benzonatate, guaifenesin, bromhexinehydrochloride, ambroxol hydrochloride, acetylcysteine, ethylcysteinehydrochloride, carbocysteine and the like.

(21) Sedatives

Chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital,amobarbital, pentobarbital, thiopental sodium, thiamylal sodium,nitrazepam, estazolam, flunitrazepam, haloxazolam, triazolam,flunitrazepam, bromovalerylurea, chloral hydrate, triclofos sodium andthe like.

(22) Anesthetics

(22-1) Local Anesthetics

Cocaine hydrochloride, procaine hydrochlodie, lidocaine, dibucainehydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride,bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethylaminobenzoate, oxethazaine and the like.

(22-2) Systemic Anesthetics

-   [1] Inhalation anesthetics (e.g., ether, halothane, nitrous oxide,    enflurane, enflurane),-   [2] Intravenous anesthetics (e.g., ketamine, droperidol, thiopental    sodium, thiamylal sodium, pentobarbital) and the like.    (23) Anxiolytic Agents

Diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam,cloxazolam, clotiazepam, prazepam, etizolam, fludiazepam, hydroxyzineand the like.

(24) Antipsychotic Agents

Chlorpromazine hydrochloride, prochloroperazine, trifluoperazine,thioridazine hydrochloride, perphenazine hydrochloride, perphenazinemaleate, fluphenazine enanthate, prochloperazine maleate,levomepromazine maleate, promethazine hydrochloride, haloperidol,bromperidol, spiperone, reserpine, clomipramine hydrochloride,sulpiride, zotepine and the like.

(25) Muscle Relaxants

Pridinol, tubocurarine, pancuronium, tolperisone hydrochloride,chlorphenesin carbamate, baclofen, chlormezanone, mephenesin,chlozoxazone, eperisone, tizanidine and the like.

(26) Antiepileptic Agents

Phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, trimethadione,carbamazepine, phenobarbital, primidone, sulthiam, sodium valproate,clonazepam, diazepam, nitrazepam and the like.

(27) Antidepressants

Imipramine, clomipramine, noxiptiline, pheneridine, amitriptylinehydrochloride, nortriptyline hydrochloride, amoxapine, mianserinhydrochloride, maprotiline hydrochloride, sulpiride, fluvoxaminemaleate, trazodone hydrochloride and the like.

(28) Anesthetic Antagonists

Levallorphan, nalorphine, naloxone and their salts and the like.

(29) Antitumor Agents

6-O-(N-Chloroacetylcarbamoyl), fumagilol, bleomycin, methotrexate,actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarcinostatin,cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil,picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin,doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycinhydrochloride, peplomycin sulfate, vincristine sulfate, vinblastinesulfate, irinotecan hydrochloride, cyclophosphamide, melphalan,zisulphan, thiotepa, procarbazine hydrochloride, cisplatin,azathioprine, mercaptoprine, tegafur, carmofur, cytarabine,methyltestosterone, testosterone propionate, testosterone enanthate,mepitiostane, fosfestrol, chlormadinone acetate, leuproline acetate,buserelin acetate and the lile.

(30) Anti-allergic Agents

Diphenhydramine, chlorphenyramine, tripelennamine, methodiramine,clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglicate,tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine,mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlukasthydrate, seratrodast and the like.

(31) Lipid-soluble Vitamins

-   [1] Vitamin As: Vitamin A₁, Vitamin A₂ and retinol palmitate.-   [2] Vitamin Ds: Vitamin D₁, D₂, D₃, D₄ and D₅.-   [3] Vitamin Es: α-tocopherol, β-tocopherol, γ-tocopherol,    δ-tocopherol, dl-α-tocopherol nicotinate.-   [4] Vitamin Ks: Vitamin K₁, K₂, K₃ and K₄.-   [5] Folic acid (vitamin M) and the like.    (32) Vitamin Derivatives

Various vitamin derivatives such as vitamine D₃ derivarives including5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol,1-α-hydroxycholecalciferol and the like, vitamin D₂ derivativesincluding 5,6-trans-ergocalciferol and the like.

(33) Anti-asthmatic Agents

Isoprenaline hydrochloride, salbutamol sulfate, procaterolhydrochloride, terbutaline sulfate, trimetoquinol hydrochloride,tubobuterol hydrochloride, orciprenaline sulfate, fenoterolhydrobromide, ephedrine hydrochloride, ipratropium bromide, oxitropiumbromide, flutropium bromide, theophylline, aminophylline, sodiumcromoglicate, tranilast, repirinast, amlexanox, ibudilast, ketotifen,terfenadine, mequitazine, pranlukast hydrate, seratrodast,dexamethasone, prednisolone, hydrocortisone, beclometaason dipropionateand the like,

(34) Pollakiuria/incontinence Treating Agents

Flavoxate hydrochloride and the like.

(35) Atopic Dermatitis Treating Agents

Sodium cromoglicate and the like.

(36) Allergic Rhinitis Treating Agents

Sodium cromoglicate, chlorphenyramine maleate, alimemazine tartrate,clemastine fumarate, homochlorcyclizine hydrochloride, terfenadine,mequitazine and the like.

(37) Others

Hydroxycam, diaserine, megestrol acetate, nicergoline, plostaglandinsand the like.

By means of a combination of a compound of the present invention with aconcomitant drug, for example, the following effects are experienced.

-   (1) The dose or the side effect of a compound of the present    invention or a salt thereof or a prodrug thereof and a concomitant    drug can be lower than those when given alone.-   (2) A synergistic therapeutic effect can be obtained against acute    coronary artery syndrome such as acute myocardial infarction and    unstable angina, peripheral artery occlusion, restenosis after    percutaneous transluminal coronary angioplasty (PTCA),    hypercholesteremia, atherosclerosis, ischemic heart disease such as    myocardial infarction and angina pectoris, cerebrovascular    impairment such as cerebral infarction and apoplexy as well as    thrombus formation.-   (3) A wide therapeutic effect can be obtained against various    diseases accompanied with diseases developed in association with    acute coronary artery syndrome such as acute myocardial infarction    and unstable angina, peripheral artery occlusion, restenosis after    percutaneous transluminal coronary angioplasty (PTCA),    hypercholesteremia, atherosclerosis, ischemic heart disease such as    myocardial infarction and angina pectoris, cerebrovascular    impairment such as cerebral infarction and apoplexy as well as    thrombus formation.

When using a compound of the present invention in combination with aconcomitant drug, the timings of the administrations of the compound ofthe present invention and the concomitant drug are not particularlylimited, and the compound of the present invention or its pharmaceuticalcomposition and the concomitant drug or its pharmaceutical compositioncan be given to a subject simultaneously or at a certain time interval.The dose of a concomitant drug may be in accordance with a dose employedclinically, and selected appropriately depending on the target, route,disease, combination and the like.

The administration mode of the concomitant formulation of the presentinvention is not particularly limited, provided that the compound of thepresent invention and the concomitant drug are combined uponadministration. Such an administration mode may, for example, be (1) anadministration of a single formulation obtained by formulating acompound of the present invention and a concomitant drug simultaneously,(2) a simultaneous administration via an identical route of twoformulations obtained by formulating a compound of the present inventionand a concomitant drug separately, (3) a sequential and intermittentadministration via an identical route of two formulations obtained byformulating a compound of the present invention and a concomitant drugseparately, (4) a simultaneous administration via different routes oftwo formulations obtained by formulating a compound of the presentinvention and a concomitant drug separately, (5) a sequential andintermittent administration via different routes of two formulationsobtained by formulating a compound of the present invention and aconcomitant drug separately (for example, inventive compound or itspharmaceutical composition followed by concomitant drug or itspharmaceutical composition, or inverse order) and the like.

A concomitant formulation of the present invention has a low toxicity,and thus a compound of the present invention and/or a concomitant drugdescribed above are mixed with a pharmacologically acceptable carrier inaccordance with a method known per se to form a pharmaceuticalcomposition, for example, a tablet (including sugar-coated andfilm-coated tablets), powder, granule, capsule (including soft capsule),solution, injection formulation, suppository, sustained releaseformulation and the like, which can safely be given orally orparenterally (e.g., topically, rectally, intravenously). An injectionformulation may be given intravenously, intramuscularly, subcutaneously,into an organ, or directly into a lesion.

A pharmacologically acceptable carrier which may be employed forproducing a concomitant formulation of the present invention may, forexample, be various organic and inorganic carrier materials employedcustomarily as pharmaceutical materials such as excipients, lubricants,binders and disintegrants in a solid formulation, solvents, dissolutionaids, suspending agents, isotonicity imparting agents, bufferring agentsand analgesic agents in a liquid formulation. Furthermore, otheradditives such as ordinary preservatives, antioxidants, colorants,sweeteners, adsorbents, wetting agents may also be added in suitableamounts.

An excipient may, for example, be lactose, sugar, D-mannitol, starch,corn starch, crystalline cellulose, light silicate anhydride and thelike.

A lubricant may, for example, be magnesium stearate, calcium stearate,talc, colloidal silica and the like.

A binder may, for example, be crystalline cellulose, sugar, D-mannitol,dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,polyvinyl pyrrolidone, starch, sucrose, gelatin, methyl cellulose,sodium carboxymethyl cellulose and the like.

A disintegrant may, for example, be starch, carboxymethyl cellulose,calcium carboxymethyl cellulose, sodium carboxymethyl starch,L-hydroxypropyl cellulose and the like.

A solvent may, for example, be water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil and the like.

A dissolution aid may, for example, be polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate and thelike.

A suspending agent may, for example, be a surfactant such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzethonium chloride, glycerinmonostearate and the like; hydrophilic polymer such as polyvinylalcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose and the like.

An isotonicity imparting agent may, for example, be glucose, D-sorbitol,sodium chloride, glycerin, D-mannitol and the like.

A buffering agent may, for example, be a buffer solution of a phosphate,acetate, carbonate, citrate and the like.

An analgesic may, for example, be benzyl alcohol.

A preservative may, for example, be a p-oxybenzoate, chlorobutanol,benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid andthe like.

An antioxidant may, for example, be a sulfite, ascorbic acid,α-tocopherol and the like.

The ratio between a compound of the present invention and a concomitantdrug in a concomitant formulation of the present invention may beselected appropriately on the basis of the target, route and disease.

For example, the amount of a compound of the present invention containedin a concomitant formulation of the present inventionis usually about0.01 to 100% by weight, preferably about 0.1 to about 50% by weight,more preferably about 0.5 to about 20% by weight based on the entireformulation, although it may vary depending on the dosage form.

The amount of an concomitant drug contained in a concomitant formulationof the present invention is usually about 0.01 to 100% by weight,preferably about 0.1 to about 50% by weight, more preferably about 0.5to about 20% by weight based on the entire formulation, although it mayvary depending on the dosage form.

The amount of an additive such as a carrier contained in a concomitantformulation of the present inventionis usually about 1 to about 99.99%by weight, preferably about 10 to about 90% by weight based on theentire formulation, although it may vary depending on the dosage form.

Similar amounts may be employed also when a compound of the presentinvention and a concomitant drug are formulated separately.

Such a formulation can be produced by a method known per se which isemployed usually in a pharmaceutical process.

For example, a compound of the present invention and a concomitant drugcan be formulated with a dispersant (e.g., Tween 80 (ATLAS POWDER, USA),HCO60 (NIKKO CHEMICALS), polyethylene glycol, carboxymethyl cellulose,sodium alginate, hydroxypropylmethyl cellulose, dextrin), a stabilizer(e.g., ascorbic acid, sodium pyrosulfite), a surfactant (e.g.,polysorbate 80, macrogol), a solubilizing agent (e.g., glycerin,ethanol), a buffering agent (phosphoric acid and its alkali metal salt,citric acid and its alkali metal salt and the like), an isotonizingagent (e.g., sodium chloride, potassium chloride, mannitol, sorbitol,glucose), a pH modifier (e.g., hydrochloric acid, sodium hydroxide), apreservative (e.g., ethyl p-oxybenzoate, benzoic acid, methylparabene,propylparabene, benzyl alcohol), a solubilizer (e.g., concentratedglycerin, meglumine), a solubilizing aid (e.g., propylene glycol,sugar), an analgesic (e.g., glucose, benzyl alcohol) into an aqueousformulation for injection, or dissolved, suspended or emulsified in avegetable oil such as olive oil, sesame oil, cottonseed oil and corn oiland in a solubilizing aid such as propylene glycol to form an oilyformulation, whereby producing an injection formulation.

In order to obtain an oral dosage form, a method known per se isemployed to compact an inventive compound or a concomitant drug forexample with an excipient (e.g., lactose, sugar, starch), a disintegrant(e.g., starch, calcium carbonate), a binder (e.g., starch, gum Arabic,carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose)or a glidant (e.g., talc, magnesium stearate, polyethylene glycol 6000)into a desired shape, which is then, if necessary, coated for thepurpose of a taste masking, an enteric property or a sustained releaseperformance by means of a coating method known per se, whereby obtainingan oral dosage form. Such a coating may, for example, behydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose,hydroxypropyl cellulose, polyoxyehtylene glycol, Tween 80, Pluronic F68,cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate,hydroxymethyl cellulose acetate succinate, Eudragit (Rohm, German,methacrylic/acrylic acid copolymer) and a colorant (e.g., iron oxidered, titanium dioxide). An oral dosage form may be an instantaneousrelease formulation or a sustained release formulation.

For example, in order to obtain a suppository, a method known per se isemployed to convert an inventive compound or concomitant drug into anoily or aqueous solid, semi-solid or liquid suppository. An oily baseemployed in a composition described above may, for example, be a higherfatty acid glyceride [e.g., cocoa butter, UITEPSOL (DYNAMITE NOVEL,Germany)], a medium fatty acid [e.g., MIGRIOL (DYNAMITE NOVEL,Germany)], or a vegetable oil (e.g., sesame oil, soybean oil, cottonseedoil). An aqueous base may, for example, be polyethylene glycol andpropylene glycol, and an aqueous gel base may, for example, be naturalgums, cellulose derivatives, vinyl polymers and acrylic acid polymers.

A sustained release formulation described above may, for example, be asustained-release microcapsule.

While a sustained-release microcapsule can be obtained by a method knownper se, a sustained release formulation shown in Section [2] describedbelow is formed and administered in a preferred case.

An compound of the present invention is preferably formulated as an oraldosage form such as a solid formulation (e.g., powder, granule, tablet,capsule), or as a rectal formulation such as a suppository. An oraldosage form is particularly preferred.

A concomitant drug can be formulated into a dosage form described abovebased on the type of the drug.

The followings are the descriptions with regard to [1] an injectionformulation of a compound of the present invention or a concomitant drugand a method for producing the same, [2] a sustained-release orimmediate release formulation of a drug of a compound of the presentinvention or a concomitant drug and a method for producing the same, [3]a sublingual, buccal or oral instantaneous disintegration formulationsemploying of a compound of the present invention or a concomitant drugand a method for producing the same, and [4] a solid dispersion of acompound of the present invention or a concomitant drug and a method forproducing the same.

[1] Injection Formulation and Method for Producing the Same

A solution obtained by dissolving a compound of the present invention ora concomitant drug in water is employed preferably. Such injectionformulation may contain a benzoate and/or a salicylate.

Said injection formulation is obtained by dissolving a compound of thepresent invention or a concomitant drug in water together with abenzoate and/or a salicylate in water as desired.

A benzoate and/or a salicylate described above may be an alkali metalsalt such as sodium and potassium salts, an alkaline earth metal saltsuch as calcium and magnesium salts, an ammonium salt, a meglumine saltas well as a salt of an organic acid such as trometamol.

The concentration of a compound of the present invention or aconcomitant drug in a injection formulation is 0.5 to 50 w/v %,preferably about 3 to 20 w/v %. The concentration of a benzoate and/or asalicylate is 0.5 to 50 w/v %, preferably 3 to 20 w/v %.

The formulation may contain additives employed customarily in ainjection formulation, such as a stabilizer (ascorbic acid, sodiumpyrosulfite and the like), a surfactant (polysorbate 80, macrogol andthe like), a solubilizing agent (glycerin, ethanol and the like), abuffering agent (phosphoric acid and its alkali metal salt, citric acidand its alkali metal salt and the like), an isotonizing agent (sodiumchloride, potassium chloride and the like), a dispersing agent(hydroxypropylmethyl cellulose, dextrin), a pH modifier (hydrochloricacid, sodium hydroxide and the like), a preservative (ethylp-oxybenzoate, benzoic acid and the like), a solubilizer (concentratedglycerin, meglumine and the like), a solubilizing aid (propylene glycol,sugar and the like), a painkiller (glucose, benzyl alcohol and the like)as appropriate. Any of these additives is added in an amount employedcustomarily in a formulation for injection.

The pH of an injection formulation is adjusted at 2 to 12, preferably2.5 to 8.0 with a pH modifier.

An injection formulation is obtained by dissolving a compound of thepresent invention or a concomitant drug if desired together with abenzoate and/or salicylate in water if desired together with theadditives listed above. These components may be dissolved in any orderas appropriate similarly to a customary preparation of a formulation forinjection.

An aqueous solution for injection is preferably warmed, and given as aformulation for injection after sterilizing by filtration or autoclavesimilarly to a customary formulation for injection.

An aqueous solution for injection is preferably autoclaved at 100 to121° C. for 5 to 30 minutes.

A formulation may be present as a solution imparted with anantibacterial activity for the purpose of using several times in divideddoses.

[2] Sustained-release or Immediate Release Formulation and Method forProducing the Same

A sustained release formulation obtained by coating a core containing acompound of the present inventiond or a concomitant drug with a coatingagent such as a water-insoluble material or a swelling polymer asdesired is employed preferably. For example, a sustained-release oralformulation of a single daily dose is preferred.

A water-insoluble material employed as a coating agent may, for example,be cellulose ethers such as ethyl cellulose and butyl cellulose,cellulose esters such as cellulose acetate and cellulose propionate,polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate,acrylic acid-based polymers such as an acrylic acid/methacrylic acidcopolymer, a methyl methacrylate copolymer, an ethoxyethylmethacrylate/cinnamoethyl methacrylate/aminoalkyl methacrylatecopolymer, polyacrylic acid, polymethacrylic acid, a metacrylic acidalkylamide copolymer, a poly(methyl methacrylate), a polymethacrylate, apolymethacrylamide, an aminoalkyl methacrylate copolymer, apoly(methacrylic anhydride), a glycidyl methacrylate copolymer,especially, a series of Eudragit (Rohm Pharma) such as Eudragit RS-100,RL-100, RS-30D, RL-30D, RL-PO, RS—PO (ethyl acrylate/methylmethacrylate/chlorotrimethyl methacrylate/ethyl ammonium copolymer) andEudragit NE-30D (methyl methacrylate/ethyl acrylate copolymer),hydrogenated oils such as a hydrogenated castor oil (e.g., Lubri wax(FREUND), waxes such as carnauba wax, a fatty acid glycerin ester andparaffin and a polyglycerin fatty acid ester.

As a swelling polymer, a polymer having an acidic leaving group andexhibiting a pH-dependent swelling is preferred, and an acidic leavinggroup-bearing polymer which undergoes a less swelling at an acidic pHsuch as in stomach but is swollen extensively at a neutral pH such as insmall and large intestines is preferred.

Such polymer having an acidic leaving group and exhibiting apH-dependent swelling may, for example, be a crosslinked polyacrylicacid polymer such as Carbomers 934P, 940, 941, 974P, 980, 1342 and thelike, Polycarbophil and Carcium Polycarbophil (BF Goodrioch), HIBISWakos 103, 104, 105 and 304 (Wako Pure Chemical).

A coating agent employed in a sustained release formulation may furthercontain a hydrophilic material.

Such hydrophilic material may, for example, be a polysaccharide whichmay have a sulfate group such as pullulan, dextrin and alkali metalalginates, a polysaccharide having a hydroxyalkyl group or acarboxyalkyl group such as hydroxypropyl cellulose, hydroxypropylmethylcellulose and sodium carboxymethyl cellulose as well as methylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol and polyethyleneglycol.

The water-insoluble material content in a coating agent of a sustainedrelease formulation is about 30 to about 90% (w/w), preferably about 35to about 80% (w/w), more preferably about 40 to about 75% (w/w), and theswelling polymer content is about 3 to about 30% (w/w), preferably about3 to about 15% (w/w). A coating agent may further contain a hydrophilicmaterial, the content of which in the coating is about 50% (w/w) orless, preferably about 5 to about 40% (w/w), more preferably about 5 toabout 35% (w/w). A % (w/w) referred here means a % by weight based onthe coating composition which is the remainder of the coating solutionafter deleting any solvent (e.g., water and a lower alcohol such asmethanol and ethanol).

A sustained release formulation is produced, as exemplified below, bypreparing a core containing a drug followed by coating a resultant corewith a coating solution obtained by melting a water-insoluble materialor a swelling polymer or by dissolving or dispersing such material in asolvent.

I. Drug-containing Core Preparation

While a coated drug-containing core (hereinafter sometimes referred tosimply as a core) may be in any non-limiting shape, it is formedpreferably as a particle such as a granule or a fine particle.

When a core is a granule or a fine particle, it has a mean particle sizepreferable of about 150 to 2,000 μm, more preferably about 500 to 1,400μm.

A core can be prepared by a standard method. For example, a drug iscombined with suitable excipient, binder, disintegrant, glidant,stabilizer and the like, and then subjected to a wet extrusiongranulation or a fluidized bed granulation.

The drug content in a core is about 0.5 to about 95% (w/w), preferablyabout 5.0 to about 80% (w/w), more preferably about 30 to about 70%(w/w).

An excipient contained in a core may, for example, be a saccharide suchas sucrose, lactose, mannitol and glucose, starch, crystallinecellulose, calcium phosphate and corn starch. Among these, crystallinecellulose and corn starch are preferred.

A binder may, for example, be polyvinyl alcohol, hydroxypropylcellulose, polyethylene glycol, polyvinyl pyrrolidone, Pluronic F68, gumArabic, gelatin and starch. A disintegrant -may, for example, be calciumcarboxymethyl cellulose (ECG505), sodium croscarmellose (Ac-Di-Sol),crosslinked polyvinyl pyrrolidone (crospovidone) and a low-substitutedhydroxypropyl cellulose (L-HPC). Among these, hydroxypropyl cellulose,polyvinyl pyrrolidone and a low-substituted hydroxypropyl cellulose arepreferred. A glidant and an anticoagulant may, for example, be talc,magnesium stearate and its inorganic salts, and a lubricant may, forexample, be polyethylene glycol. A stabilizer may, for example, be anacid such as tartaric acid, citric acid, succinic acid, fumaric acid andmaleic acid.

In addition to the methods described above, other methods can beemployed to form a core, such as an agitating granulation method whereinan inert carrier particle as a seed for the core is sprayed with abinder dissolved in a suitable solvent such as water and a lower alcohol(e.g., methanol and ethanol) with being supplemented portionwise with adrug or a mixture thereof with an excipient and a glidant as well as apan coating method, a fluidized bed coating method and a meltinggranulation method. An inert carrier particle -may, for example, be oneprepared from sugar, lactose, starch, crystalline cellulose and waxes,and has a mean particle size preferably of about 100 μm to about 1,500μm.

In order to separate a drug contained in a core from a coating, thesurface of the core may be covered with a protective material. Suchprotective material may, for example, be a hydrophilic materialdescribed above and a water-insoluble material. A preferred protectivematerial is polyethylene glycol or a polysaccharide having ahydroxyalkyl group or a carboxyalkyl group, more preferably,hydroxypropylmethyl cellulose and hydroxypropyl cellulose. Theprotective material may contain, as a stabilizer, an acid such astartaric acid, citric acid, succinic acid, fumaric acid and maleic acid,as well as a glidant such as talc. A protective material, when employed,is coated at a rate of about 1 to about 15% (w/w), preferably about 1 toabout 10% (w/w), more preferably about 2 to about 8% (w/w) based on acore.

A protective material can be coated by a standard coating method, andspecifically a core is spray-coated with the protective material by afluidized bed coating method and a pan coating method.

II. Coating of Core with Coating Agent

A core obtained as described above in Section I is coated with a coatingsolution containing a water-insoluble material, a pH-dependent swellingpolymer and a hydrophilic material being melted therein by heating orbeing dissolved or dispersed in a solvent to obtain a sustained releaseformulation.

A method for coating a core with a coating solution may, for example, bea spray coating.

The ratio between a water-insoluble material, a swelling polymer and ahydrophilic material in a coating solution may be selected appropriatelyin such a manner that respective contents in the coating become thosespecified above.

The rate of coating agent is about 1 to about 90% (w/w), preferablyabout 5 to about 50% (w/w), more preferably about 5 to about 35% (w/w)based on the core (excluding the protective material coating).

A solvent for a coating solution is water or an organic solvent, whichmay be employed alone or in combination with each other. The ratiobetween water and the organic solvent when being employed in combination(water/organic solvent: weight ratio) may vary from 1 to 100%, and ispreferably 1 to about 30%. While said organic solvent is not limitedparticularly as long as it can dissolve a water-insoluble material, itmay, for example, be a lower alcohol such as methyl alcohol, ethylalcohol, isopropyl alcohol and n-butyl alcohol, a lower alkanone such asacetone, as well as acetonitrile, chloroform, ethylene chloride and thelike. Among those listed above, a lower alcohol is preferred, with ethylalcohol and isopropyl alcohol being especially preferred. Water and amixture of water and an organic solvent are employed preferably assolvents for a coating. In such a case, an acid such as tartaric acid,citric acid, succinic acid, fumaric acid and maleic acid may be added tothe coating solution for the purpose of stabilizing the coatingsolution.

When the coating is effected by a spray coating, a standard coatingmethod can be employed, and specifically a core is sprayed with acoating by a fluidized bed coating method and a pan coating method.During this process, a lubricant such as talc, titanium oxide, magnesiumstearate, calcium stearate and light silicic anhydride and a plasticizersuch as glycerin fatty ester, hardened castor oil, triethyl citrate,cetyl alcohol and stearyl alcohol may also be added.

After coating with a coating agent, an antistatic agent such as a talcmay also be incorporated if necessary.

An instantaneous release formulation may be a liquid (solution,suspension, emulsion) or a solid (particle, pill, tablet). While an oralformulation and a parenteral formulation such as an injectionformulation may be employed, an oral formulation is preferred.

An instantaneous release formulation may usually contain, a carrier,additive and excipient (hereinafter sometimes abbreviated as excipient)which are employed customarily in the pharmaceutical field, in additionto a drug which is an active ingredient. Such a formulation excipient isnot limited particularly as long as it is an excipient employed usuallyas a formulation excipient. For example, an excipient for an oral solidformulation may be lactose, starch, corn starch, crystalline cellulose(Asahi Kasei, Avicel PH101 and the like), powder sugar, granulatedsugar, mannitol, light silicic anhydride, magnesium carbonate, calciumcarbonate, L-cysteine and the like, with corn starch and mannitol beingpreferred. Any of these excipients may be employed alone or incombination with each other. The amount of an excipient may, forexample, be about 4.5 to about 99.4 w/w %, preferably about 20 to about98.5 w/w %, more preferably about 30 to about 97 w/w %, based on theentire amount of an instantaneous release formulation.

The drug content in an instantaneous release formulation may be selectedwithin the range from about 0.5 to about 95%, preferably about 1 toabout 60%, based on the entire amount of an instantaneous releaseformulation.

An oral solid instantaneous release formulation contains a disintegrantin addition to the ingredients described above. Such a disintegrant may,for example, be calcium carboxymethyl cellulose (GOTOKUYAKUHIN, ECG505),sodium croscarmellose (for example, Asahi Kasei, Ac-Di-Sol),crospovidone (for example, BASF, Coridon CL), low-substitutedhydroxypropyl cellulose (Shin-Etsu Chemical K.K.), carboxymethyl starch(Matsutani Chemical Industry K.K.), sodium carboxymethyl starch (KimuraIndusty K.K., EXORITAB), partial α starch (Asahi Kasei, PCS) and thelike, any of which may, for example, be brought into contact with waterto effect water absorption or swelling, or to make a channel between acore-forming active ingredient and an excipient, whereby disintegratinga granule. Any of these disintegrants may be employed alone or incombination with each other. While the amount of a disintegrant to beincorporated may be selected appropriately based on the type and theamount of the drug employed, it may, for example, be about 0.05 to about30 w/w %, preferably about 0.5 to about 15 w/w % based on the entireamount of an instantaneous release formulation.

An oral solid instantaneous release formulation contains additivesemployed customarily in a solid formulation if desired in addition tothe components described above. Such additives may, for example, bebinders (for example, sucrose, gelatin, powdery gum Arabic, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,carboxymethyl cellulose, polyvinylpyrrolidone, pulluran, dextrin),lubricants (for example, polyethylene glycol, magnesium stearate, talc,light silicic anhydride (for example, aerosil (NIPPON AEROSIL)),surfactants (for example, anionic surfactants such as sodiumalkylsulfate, nonionic surfactants such as polyoxyethylene fatty esterand polyoxyethylene sorbitan fatty ester, polyoxyethylene castor oilderivatives), colorants (for example, tar-based colorants, caramel, redocher, titanium oxide, ribofravin), if necessary together withseasonings (for example, sweetener and flavor), adsorbents,preservatives, wetting agents, antistatic agents and the like. As astabilizer, an organic acid such as tartaric acid, citric acid, succinicacid and fumaric acid may also be added.

A binder described above are preferably hydroxypropyl cellulose,polyethylene glycol and polyvinylpyrrolidone.

An instantaneous formulation can be prepared based on an ordinaryformulation technology by mixing the components described above andkneading if necessary and then molding. Such a mixing may beaccomplished by an ordinary method, such as mixing and kneading.Typically, when an instantaneous release formulation is formed as aparticle, then a method similar to that for preparing a core of asustained release formulation described above is employed to mix thematerials using a vertical granulator, multi-purpose kneader (HATAKETEKKOSHO), fluidized bed granulator FD-5S (Powrex) and the like, afterwhich a granulation is effected using a wet extrusion granulation or afluidized bed granulation.

Each of an instantaneous release formulation and a sustained releaseformulation thus obtained may be formulated separately by a standardmethod as it is or in combination with an excipient as appropriate andthen provided as a final formulation for simultaneous administration orintermittent sequential administration, or the both may be formulated ina single oral formulation (e.g., granule, fine powder, tablet, capsule)as they are or in combination with an excipient as appropriate. The bothformulation may be formulated also as granules or fine powders, whichare then filled in a single capsule for oral administration.

[3] Sublingual, Buccal or Intraoral Instantaneous DisintegrationFormulations and Method for Producing the Same

Any of sublingual, buccal or intraoral instantaneous disintegrationformulations may be a solid formulation such as a tablet, or may be anoral mucosa plaster (film).

Each of sublingual, buccal or intraoral instantaneous disintegrationformulations is preferably a formulation containing an inventivecompound or a concomitant drug together with an excipient. An auxiliaryagent may also be contained such as a lubricant, iotonizing agent,hydrophilic carrier, water-dispersible polymer and stabilizer. For thepurpose of promoting the absorption and enhancing the bioavailability,β-cyclodextrin or β-cyclodextrin derivatives (e.g.,hydroxypropyl-β-cyclodextrin) may also be contained.

Such an excipient -may, for example, be lactose, sugar, D-mannitol,starch, crystalline cellulose, light silicic anhydride and the like. Alubricant may, for example, be magnesium stearate, calcium stearate,talc, colloidal silica and the like, with magnesium stearate andcolloidal silica being preferred. An iotonizing agent may, for example,be sodium chloride, glucose, fructose, mannitol, sorbitol, lactose,saccharose, glycerin and urea, with mannitol being preferred especially.A hydrophilic carrier may, for example, be a swelling hydrophiliccarrier such as a crystalline cellulose, ethyl cellulose, crosslinkedpolyvinyl pyrrolidone, light silicic anhydride, silicic acid, dicalciumphosphate, calcium carbonate and the like, with a crystalline cellulose(e.g., microcrystalline cellulose) being preferred. A water-dispersiblepolymer -may, for example, be a gum (e.g., tragacanth gum, acacia gum,guar gum), alginate (e.g., sodium alginate), cellulose derivative (e.g.,methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose), gelatin,water-soluble starch, polyacrylic acid (e.g., carbomer), polymethacrylicacid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone,polycarbophil, ascorbate palmitate ester and the like, withhydroxypropylmethyl cellulose, polyacrylic acid, alginate, gelatin,carboxymethyl cellulose, polyvinylpyrrolidone and polyethylene glycolbeing preferred. Hydroxypropylmethyl cellulose is especially preferred.A stabilizer may, for example, be cysteine, thiosorbitol, tartatic acid,citric acid, sodium carbonate, ascrobic acid, glycine and sodiumsulfite, with citric acid and ascorbic acid being preferred especially.

Each of sublingual, buccal or intraoral instantaneous disintegrationformulations can be produced by mixing an inventive compound orconcomitant drug with an excipient by a method known per se. If desired,an auxiliary agent described above, such as lubricant, iotonizing agent,hydrophilic carrier, water-dispersible polymer, stabilizer, colorant,sweetener and preservative, may also be incorporated. After mixing thecomponents described above simultaneously or at a certain time interval,the mixture is compacted and molded into each of sublingual, buccal orintraoral instantaneous disintegration formulations. For the purpose ofobtaining a suitable hardness, a solvent such as water and alcohol maybe employed to wet the mixture before or after the tablet impaction, andthen dried finally.

When a oral mucosa plaster (film) is to be molded, an inventive compoundor concomitant drug and a water-dispersible polymer (preferably,hydroxypropyl cellulose, hydroxypropylmethyl cellulose) and excipientdescribed above are dissolved in a solvent such as water, and then theresultant solution is casted into a film. Additives may also be addedsuch as plasticizers, stabilizers, antioxidants, preservatives,colorants, buffering agents and sweeteners. A glycol such aspolyethylene glycol or propylene glycol may be added for the purpose ofimparting a film with an appropriate elasticity, and a bioadhesivepolymer (e.g., polycarbophile, carbopol) may be added for the purpose ofenhancing the adhesion of the film to the oral mucosal lining. Thecasting may be accomplished by pouring a solution onto a non-adhesivesurface, spreading the solution using a coater such as a doctor bladeinto a uniform thickness (preferably about 10 to 1000 microns), and thendrying the solution to form a film. The film thus formed is dried atroom temperature or with warming, and then cut into pieces each having adesired surface area.

A preferred intraoral instantaneous disintegration formulation may, forexample, be a rapid diffusion formulation in the form of a solid networkconsisting of an inventive compound or concomitant drug together with awater-soluble or water-diffusable carrier which is inert to theinventive compound or concomitant drug. Said network is obtained bysublimating a solvent from a solid composition consisting of a solutionof an inventive compound or concomitant drug in a suitable solvent.

In addition to an inventive compound or concomitant drug, amatrix-forming agent and a secondary component are contained preferablyin the composition of said intraoral instantaneous disintegrationformulation.

Said matrix-forming agents may, for example, be an animal or vegetableprotein such as a gelatin, dextrin and soybean, wheat and psyllium seedproteins; a gummy material such as gum Arabic, guar gum, agar andxanthane gum; polysaccharide; alginate; carboxymethyl cellulose;carrageenan; dextran; pectin; synthetic polymer such aspolyvinylpyrrolidone; a material derived from a gelatin-gum Arabiccomplex. Those which are also included are saccharides such as mannitol,dextrose, lactose, galactose and trehalose; cyclic saccharides such ascyclodextrin; inorganic salts such as sodium phosphate, sodium chlorideand aluminium silicate; amino acids having 2 to 12 carbon atoms such asglycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline,L-isoleucine, L-leucine and L-phenylalanine.

One or more matrix-forming agents may be introduced into a solution orsuspension before solidification. Such a matrix-forming agent may bepresent in addition to a surfactant, or may be present in the absence ofthe surfactant. The matrix-forming agent serves not only to form amatrix itself, but also to aid in maintaining an inventive compound orconcomitant drug as being diffused in the solution or suspension.

A secondary agent may be contained in a composition such as apreservative, antioxidant, surfactant, thickening agent, colorant, pHmodifier, flavor, sweetener or taste masking agent. A suitable colorantmay, for example, be iron oxide red, black and yellow, FD&C dyesavailable from ERIS AND EVERALD such as FD&C Blue No.2 and FD&C RedNo.40. A suitable flavor may, for example, be mint, raspberry, licorice,orange, lemon, grape fruit, caramel, vanilla, cherry and grape flavor aswell as a combination thereof. A suitable pH modifier may, for example,be citric acid, tartaric acid, phosphoric acid, hydrochloric acid andmaleic acid. A suitable sweetener may, for example, be aspartame,acesulfame K and thaumatine. A suitable taste masking agent may, forexample, be sodium bicarbonate, ion exchange resin, cyclodextrininclusion compound, adsorbent and microencapsulated apomorphine.

A formulation contains an inventive compound or concomitant drug in anamount usually of about 0.1 to about 50% by weight, preferably about 0.1to about 30% by weight, and is preferably a formulation (sublingual orbuccal formulation described above) which allows 90% or more of theinventive compound or concomitant drug to be dissolved (in water) withina time period of about 1 to about 60 minutes, preferably about 1 minutesto about 15 minutes, more preferably about 2 minutes to about 5 minutes,or a intraoral instantaneous disintegration formulation whichdisintegrates within about 1 to about 60 seconds, preferably about 1 toabout 30 seconds, more preferably about 1 to about 10 seconds afterbeing placed in the oral cavity.

The amount of an excipient described above based on the entireformulation is about 10 to about 99% by weight, preferably about 30 toabout 90% by weight. The amount of β-cyclodextrin or β-Cyclodextrinderivative based on the entire formulation is about 0 to about 30% byweight. The amount of a lubricant based on the entire formulation isabout 0.01 to about 10% by weight, preferably about 1 to about 5% byweight. The amount of an isotonizing agent based on the entireformulation is about 0.1 to about 90% by weight, preferably about 10 toabout 70% by weight. The amount of a hydrophilic carrier based on theentire formulation is about 0.1 to about 50% by weight, preferably about10 to about 30% by weight. The amount of a water-dispersible polymerbased on the entire formulation is about 0.1 to about 30% by weight,preferably about 10 to about 25% by weight. The amount of a stabilizerbased on the entire formulation is about 0.1 to about 10% by weight,preferably about 1 to about 5% by weight. The formulation describedabove may further contain additives if desired such as colorants,sweeteners and preservatives.

[4] A Solid Dispersion of an Inventive Compound or a Concomitant Drugand a Method for Producing the Same

When a compound of the invention [hereinafter sometimes referred to aslipid-rich plaque regressing substance] or a concomitant drug is hardlysoluble or insoluble in water, then it may be formulated into a soliddispersion (e.g., a solid dispersion containing a hardly water-solubleor water-insoluble lipid-rich plaque regressing substance and ahydrophilic polymer).

“A solid dispersion” mentioned here means a dispersion in which one moreactive ingredients (preferably, amorphous active ingredients) isdispersed in a carrier or a matrix thereof which is inert in the form ofa solid (e.g., a hydrophilic polymer), which can be prepared for exampleby a fusion method, solvent method or fusion-solvent method (J. Pharm.Sci., Vol. 60, 1281-1301, 1971).

While the mean particle size of a solid dispersion is not limitedparticularly, the lower limit is usually about 0.05 μm or more,preferably about 0.1 μm or more, more preferably about 1 μm or more,further preferably 3 μm or more, while the upper limit is about 30 mm orless, preferably about 100 μm or less, more preferably about 50 μm orless, further preferably about 10 μm or less.

A hydrophilic polymer employed in said solid dispersion may, forexample, be a water-soluble polymer, enteric coating polymer, gastriccoating polymer and the like, with an enteric coating polymer beingemployed preferably.

A water-soluble polymer may, for example, be [1] a cellulose derivativeincluding a hydroxyalkyl cellulose such as hydroxypropyl cellulose andhydroxypropylmethyl cellulose and an alkyl cellulose such as methylcellulose and ethyl cellulose; [2] a polyalkenyl pyrrolidone such aspolyvinyl pyrrolidone; [3] a polyalkylene glycol such as polyethyleneglycol and the like.

An enteric coating polymer may, for example, be a hydroxyalkyl cellulosephthalate such as hydroxypropylmethyl cellulose phthalate; ahydroxyalkyl cellulose acetate succinate such as hydroxypropylmethylcellulose acetate succinate; a carboxyalkyl cellulose such ascarboxymethylethyl cellulose; cellulose acetate phthalate; a copolymerof ethyl acrylate and methacrylic acid such as methacrylic acidcopolymer L-100-55; a copolymer of methyl methacrylate and methacrylicacid such as methacrylic acid copolymer L, methacrylic acid copolymer Sand the like.

A gastric coating polymer may, for example, be an aminoalkylmethacrylatecopolymer E; polyvinyl acetal amino acetate and the like.

In addition, a copolymer of ethyl acrylate and methyl methacrylatecontaining a small amount of a quaternary ammonium group such asmethacrylic acid copolymer RL and methacrylic copolymer RS, ahydrophilic polymer capable of dispersing a hardly water-soluble orwater-insoluble lipid-rich plaque regressing substance such ascarboxymethyl cellulose, carboxyvinyl polymer, polyvinyl alcohol, gumarabic, sodium alginate, alginic acid propylene glycol ester, agar,gelatin, chitosan and the like may be employed. Any of these hydrophilicpolymers can be employed in combination with each other.

Among those listed above, preferred hydrophilic polymers are ahydroxyalkyl cellulose, alkyl cellulose, polyalkenyl pyrrolidone,polyalkylene glycol, methacrylic acid copolymer and carboxymethylcellulose and the like, and those preferred especially arehydroxypropylmethyl cellulose phthalate, polyvinyl pyrrolidone,hydroxypropylmethyl cellulose, carboxymethylethyl cellulose, methacrylicacid copolymer L and the like.

Any of the solid dispersions described above may contain additivesemployed generally in the field of the pharmaceutical formulations.

Such additives are pharmaceutically acceptable carriers such as variousorganic and inorganic carrier materials employed customarily aspharmaceutical materials, and are incorporated as excipients,lubricants, binders, disintegrants and surfactants. If desired,pharmaceutical additives such as preservatives, antioxidants, colorantsand sweeteners may also be added.

Preferred examples of excipients are lactose, sugar, D-mannitol, starch,crystalline cellulose, sucrose, porous starch, mannitol, calciumsilicate (trade name: Fluorite RE), magnesium methasilicate aluminate(trade name: NEUSILIN), light silicic anhydride (trade name: CYSILIA),sugar/starch spherical granule (trade name: nonpareil), crystallinecellulose/carboxymethyl cellulose (trade name: Avicel RC), hydroxypropylstarch and the like.

Preferred examples of lubricants are magnesium stearate, calciumstearate, talc, colloidal silica and the like.

Preferred examples of binders are crystalline cellulose, sugar,D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinyl pyrrolidone and the like.

Preferred examples of disintegrants are starch, carboxymethyl cellulose,calcium carboxymethyl cellulose, croscarmellose sodium, sodiumcarboxymethyl starch, methyl cellulose (trade name: METHOLOSE SM),croscarmellose sodium, carmellose calcium, low-substituted hydroxypropylcellulose, sodium starch glycolate, partially alpha-derivatized starchand the like.

Lubricants employed are, for example, talc, crystalline cellulose,magnesium stearate, corn starch, magnesium oxide and the like.

Surfactants employed are, for example, polyoxyethylene polyoxypropyleneglycol (trade name: Pluronic), glycerin fatty acid ester, sucrose fattyacid ester, polyoxyethylene hydrogenated castor oil, polysorbate 80,cetanol and the like.

Preferred examples of preservatives are p-oxybenzoates, chlorobutanol,benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid andthe like.

Preferred examples of antioxidants are sulfites, ascorbic acid and thelike.

Any of these additives may be used alone or in combination with eachother.

While a solid dispersion described above can be produced by a methodknown per se, it can specifically be produced for example by a spray drymethod, solvent method such as a rotary evaporation method; a fusionmethod such as twin-screw extruder method; mixing pulverization method;ultrasonic method using an ultrasonic molding machine and the like.

More specifically, a solid dispersion described above can be produced bya solvent method shown below:

-   (1) dissolvong a lipid-rich plaque regressing substance in a    suitable organic solvent;-   (2) to this solution, adding a hydrophilic polymer to prepare a    suspension;-   (3) to this suspension or solution, adding additives such as    excipients, disintegrants, lubricants and surfactants if necessary;    and then,-   (4) distilling off the organic solvent from this homogenous    suspension under reduced pressure or atmospheric pressure by a    conventional method, for example, a spray dry method, rotary    evaporation method and the like.

For obtaining a further homogenous solid dispersion, the homogenoussuspension is prepared in Step (2) described above and then subjectedsequentially to the following steps:

-   (5) dissolving a suspension prepared in Step (2) described above in    a suitable organic solvent;-   (6) adding additives such as excipients, disintegrants, lubricants    and surfactants if necessary; and then,-   (7) distilling off the organic solvent under reduced pressure or    atmospheric pressure by a conventional method, for example, a spray    dry method, rotary evaporation method and the like.

An organic solvent employed in Step (1) described above is not limitedspecifically provided that it can dissolve a hardly water-soluble orwater-insoluble lipid-rich plaque regressing substance and a hydrophilicpolymer, and may, for example, be an alcohol such as methanol, ethanol,propanol, isopropyl alcohol, butanol, monomethoxyethanol, ethyleneglycol monomethyl ether and the like; an ether such as diethyl ether,dibutyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethyleneglycol and the like; an aliphatic hydrocarbon such as n-hexane,cyclohexane, n-heptane and the like; an aromatic hydocarbon such asbenzene, toluene, xylene and the like; a nitrite such as acetonitrile;an organic acid such as acetic acid, propionic acid and the like; anester such as ethyl acetate; an aliphatic halogenated hydrocarbon suchas dichloromethane, dichloroethane, chloroform and the like; a ketonesuch as acetone and methylethyl ketone; an amide such asdimethylformamide, dimethylacetamide and the like; or a mixture thereofin a suitable ratio. Among those listed above, a low-boiling solventsuch as a ketone or alcohol is preferred, with acetone and ethanol beingespecially preferred.

While the operating conditions such as the treatment temperature and thetreatment time period may vary depending on the starting compounds andorganic solvent employed, the treatment temperature is usually 200° C.or below.

In a fusion method, a hardly water-soluble or water-insoluble lipid-richplaque regressing substance is heated at a temperature higher than themelting point to fuse it, and then a hydrophilic polymer, and additivessuch as excipients, disintegrants, lubricants and surfactants, ifnecessary, are dissolved in it, and then it is cooled rapidly toaccomplish the production. For example, in a twin-screw extruder method,a hardly water-soluble or water-insoluble lipid-rich plaque regressingsubstance and a hydrophilic polymer, if necessary together withadditives such as excipients, disintegrants, lubricants and surfactants,are mixed mechanically and then heated under a high pressure to fuse thehardly water-soluble or water-insoluble lipid-rich plaque regressingsubstance at a temperature lower than the melting point, and then themixture is cooled rapidly to accomplish the production.

In a mixing pulverization method, a hardly water-soluble orwater-insoluble lipid-rich plaque regressing substance and a hydrophilicpolymer, if necessary together with additives such as excipients,disintegrants, lubricants and surfactants, are mixed mechanically andthen pulverized with mixing to accomplish the production.

In an ultrasonic method, a hardly water-soluble or water-insolublelipid-rich plaque regressing substance and a hydrophilic polymer, ifnecessary together with additives such as excipients, disintegrants,lubricants and surfactants, are mixed mechanically and then charged intoa mortar to pre-mold the mixture, and then irradiated with an ultrasonicwave for example by using a ultrasonic molding machine to accomplish theproduction.

The amount of a hydrophilic polymer is not limited particularly, and maybe any level as long as it can disperse a hardly water-soluble orwater-insoluble lipid-rich plaque regressing substance. For example, apreferable weight ratio of a hydrophilic polymer and a hardlywater-soluble or water-insoluble lipid-rich plaque regressing substanceis 0.01:1 to 100:1, preferably 0.02:1 to 50:1, more preferably 0.1:2 to20:1, further preferably 0.3:1 to 10:1, still further preferably 1:1 to10:1, especially 3 to 5 (especially 4):1.

While the amount of an additive is not limited particularly, apreferable weight ratio of an additive such a an excipient,disintegrant, lubricant or surfactant and a hardly water-soluble orwater-insoluble lipid-rich plaque regressing substance is usually 0.1:1to 20:1, preferably 0.3:1 to 10:1, more preferably 1:1 to 3:1.

An organic solvent employed in Step (5) described above is not limitedparticularly, and may be any solvent as long as it is capable ofdissolving the suspension in Step (2) described above such as chloroformand dichloromethane.

A solid dispersion described above can itself be used as an oralpharmaceutical formulation, and may also be formulated as a powder, finepowder, granule, tablet, capsule, injection formulation and the like byan ordinary method.

A pharmaceutical formulation containing a solid dispersion describedabove may contain the additives described above, namely, colorants,sweeteners, flavors, such as sucrose, lactose, starch, crystallinecellulose, synthetic ammonium silicate, magnesium stearate, talc andother diluents and lubricants in an oral pharmaceutical formulation. Thesurface of the formulation can be coated to obtain a sustained-releaseformulation.

Since a lipid-rich plaque regressing substance is usually hardlywater-soluble or water-insoluble, the ratio at which it is absorbedactually into blood based on the dose given orally is low, resulting ina problematically low bioavailability.

Nevertheless, various formulations obtained by converting a soliddispersion described above into various dosage forms have markedlyimproved performances of dissolution, oral absorption or(and) absorptioninto blood, when compared with a crystal of a hardly water-soluble orwater-insoluble lipid-rich plaque regressing substance itself.

Thus, a solid dispersion described above enables the solubilization of ahardly water-soluble or water-insoluble lipid-rich plaque regressingsubstance, whereby allowing the bioavailability of the hardlywater-soluble or water-insoluble lipid-rich plaque regressing substanceto be improved dramatically.

The amount of a hardly water-soluble or water-insoluble lipid-richplaque regressing substance in a solid dispersion described above mayvary depending on the dosage form, administration mode, carrier and thelike, and it is usually 0.1 to 99% by weight based on the total amountof the formulation.

The amount of a hydrophilic polymer in a solid dispersion describedabove may vary depending on the dosage form, administration mode,carrier and the like, and it is usually 1 to 99.9% by weight based onthe total amount of the formulation.

The amount of an additive in a solid dispersion described above may varydepending on the dosage form, administration mode and the like, and itis usually 0 to 99% by weight based on the total amount of theformulation.

The amount of a solid dispersion described above in an inventivepharmaceutical formulation may vary depending on the dosage form,administration mode, carrier and the like, and it is usually 0.1 to 100%by weight based on the total amount of the formulation.

The amount of additives in an inventive pharmaceutical formulation mayvary depending on the dosage form, administration mode and the like, andit is usually 0 to 99.9% by weight based on the total amount of theformulation.

While the dose of an inventive concomitant formulation may varydepending on the type of the inventive compound, the subject's age, bodyweight, condition, and the dosage form as well as administration modeand duration, for example, the daily dose in a patient havinghyperlipidemia (adult, body weight: about 60 kg) is about 0.01 to about1000 mg/kg, preferably about 0.01 to about 100 mg/kg, more preferablyabout 0.1 to about 100 mg/kg, particularly about 0.1 to about 50 mg/kg,especially about 1.5 to about 30 mg/kg as an inventive compound, whichis given intravenously at once or in several portions. It is a matter ofcourse that the dose may vary depending on various factors as describedabove, and a less amount may sometimes be sufficient and an excessiveamount should sometimes be required.

A concomitant drug may be employed in any amount within the rangecausing no problematic side effects. The daily dose of a concomitantdrug is not limited particularly and may vary depending on the severityof the disease, the subject's age, sex, body weight and susceptibilityas well as time and interval of the administration and thecharacteristics, preparation, type and active ingredient of thepharmaceutical formulation, and the daily oral dose per kg body weightin a mammal is about 0.001 to 2000 mg, preferably about 0.01 to 500 mg,more preferably about 0.1 to about 100 mg as medicaments, which is givenusually in 1 to 4 portions.

When an inventive concomitant formulation is administered, it may beadministered at the same time, but it is also possible that aconcomitant drug is first administered and then an inventive compound isadministered, or that the inventive compound is first administered andthen the concomitant drug is administered. When such an intermittentadministration is employed, the time interval may vary depending on theactive ingredient administered, the dosage form and the administrationmode, and for example, when the concomitant drug is first administered,the inventive compound may be administered within 1 minute to 3 days,preferably 10 minutes to 1 day, more preferably 15 minutes to 1 hourafter the administration of the concomitant drug. When the inventivecompound is first administered, for example, then the concomitant drugmay be administered within 1 minute to 1 day, preferably 10 minutes to 6hours, more preferably 15 minutes to 1 hour after the administration ofthe inventive compound.

In a preferred administration mode, for example, about 0.001 to 200mg/kg of a concomitant drug formulated as an oral formulation is givenorally as a daily dose, and, after about 15 minutes, about 0.005 to 100mg/kg of an inventive compound formulated as an oral formulation isgiven orally as a daily dose.

The invention is further detailed in the following Examples, FormulationExamples and Experiments, which are not intended to restrict theinvention.

A ¹H NMR spectrum was measured by VARIAN GEMINI 200 (200 MHz)spectrophotometer using tetramethylsilane as an internal standard, andentire δ values are represented in ppm. A value indicated for a solventmixture is a volume ratio of each solvent, unless otherwise specified. A% is a % by weight, unless otherwise specified. A ratio of the elutionsolvent in a chromatography on a silica gel is a volume ratio, unlessotherwise specified. Room temperature (ambient temperature) employedhere usually means a temperature from about 20 to about 30° C.

Each symbol in Examples is defined as shown below.

AcOEt: ethyl acetate, Me: methyl, Et: ethyl, THF: tetrahydrofuran, IPE:isopropylether, Et₂O: diethyl ether, decomp.: decomposition, s: singlet,d: doublet, t: triplet, q: quartet, dd: double doublet, dt: doubletriplet, m: multiplet, br: broad, J: coupling constant, Py: pyridyl,DBU: diazabicycloundecene, DMF: dimethylformamide, DPPA:diphenylphosphoryl azide, hex: hexane, Ac: acetyl, Ph: phenyl, Ts:tosyl, mCPBA: m-chloroperbenzoic acid, ^(t)Bu: tert-butyl.

EXAMPLES Reference Example 1

Synthesis of 6,7-dichloro-2-oxo-4-phenyl-2H-chromene-3-carboxylic acid

A mixture of (4,5-dichloro-2-hydroxyphenyl) (phenyl)methanone (1.5 g),diethyl malonate (1.28 ml) and DBU (0.25 ml) was stirred at 170° C. for30 minutes. The reaction mixture was dissolved in ethyl acetate (50 ml),and washed with water followed by a 1 N solution of hydrochloric acidand a saturated aqueous solution of sodium chloride. After drying overmagnesium sulfate, the solvent was distilled off under reduced presurre,and the residue was purified by a column chromatography (packing: silicagel, eluent: ethyl acetate-hexane=1:9). The resultant crude product ofethyl 6,7-dichloro-2-oxo-4-phenyl-2H-chromene-3-carboxylate wasdissolved in acetic acid (10 ml) and concentrated hydrochloric acid (5ml), and heated under reflux for 1 hour. The reaction solution wasconcentrated under reduced pressure, and the resultant residue wasdissolved in a solvent mixture of THF (10 ml) and ethyl acetate (50 ml),and then washed with water followed by a saturated aqueous solution ofsodium hydrogen carbonate and a saturated aqueous solution of sodiumchloride. After drying over magnesium sulfate, the solvent was distilledoff under reduced pressure, and the residue was purified byrecrystallization from ethyl acetate to obtain the title compound (0.65g, yield: 34%).

Melting point: 233-234° C.

NMR (CDCl₃) δ: 7.29-7.40 (3H, m), 7.48-7.58 (4H, m).

IR(KBr): 3400-2400, 1748, 1717 cm⁻¹.

Analysis for C₁₆H₈O₄Cl₂: Calcd (%): C:57.34H:2.41 Found (%):C:57.30H:2.50.

Reference Example 2-6

The compounds of table 1 were obtained by the method similar to that inReference Example 1.

TABLE 1

Ref.Ex. Yield Melting Point (° C.) number R¹ R² R³ (%)(Recrystallization solvent) 2 Cl Me H 63 227-228 (AcOEt) 3 Cl Me Me 58226-227 (AcOEt) 4 Me Me H 81 205-206 (AcOEt) 5 Me Me Me 27 222-223(AcOEt) 6 (CH₂)₄ H 7  92-93 (AcOEt)

Reference Example 7

Synthesis of (6,7-dichloro-2-oxo-4-phenyl-2H-chromen-3-yl)acetic acid

A solution of 6,7-dichloro-2-oxo-4-phenyl-2H-chromene-3-carboxylic acid(0.8 g) in THF (10 ml) was combined with DMF (1 drop) and oxalylchloride (0.31 ml), and stirred at room temperature for 1 hour. Afterthe reaction solution was concentrated under reduced pressure, theresultant residue was dissolved in THF (10 ml), and to which a solutionof diazomethane prepared from N-methyl-N′-nitro-N-nitrosoguanidine (1.68g) and potassium hydroxide (3.0 g) in ether (30 ml) was added dropwise.After the effervescence had ceased, the reaction solution wasconcentrated under reduced pressure. The resultant residue was dissolvedin methanol (50 ml), combined with silver oxide, and heated under refluxfor 30 minutes. After the insolubles were filtered off, the filtrate wasconcentrated under reduced pressure, and the residue was purified by acolumn chromatography (packing: silica gel, eluent: ethylacetate-hexane=1:4). The resultant crude product of methyl(6,7-dichloro-2-oxo-4-phenyl-2H-chromen-3-yl)acetate was dissolved inacetic acid (5 ml) and concentrated hydrochloric acid (2.5 ml), andheated under reflux for 1 hour. The reaction solution was concentratedunder reduced pressure, and the resultant residue was dissolved in asolvent mixture of THF (10 ml) and ethyl acetate (50 ml), and thenwashed with water followed by a saturated aqueous solution of sodiumhydrogen carbonate and a saturated aqueous solution of sodium chloride.After drying over magnesium sulfate, the solvent was distilled off underreduced pressure, and the residue was purified by recrystallization fromethyl acetate to obtain the title compound (0.52 g, yield: 62%).

Melting point: 222-223° C.

NMR (CDCl₃) δ: 3.43 (2H, s), 7.10 (1H, s), 7.20-7.36 (2H, m), 7.50-7.64(4H, m.).

IR(KBr): 3400-2400, 1725, 1599 cm⁻¹.

Analysis for C₁₇H₁₀O₄Cl₂.0.3H₂O Calcd (%): C:57.59H:3.01 Found (%):C:57.44H:2.99.

Reference Example 8-12

The compounds of table 2 were obtained by the method similar to that inReference Example 7.

TABLE 2

Ref.Ex. Yield Melting Point (° C.) number R¹ R² R³ (%)(Recrystallization solvent) 8 Cl Me H 50 216-217 (AcOEt) 9 Cl Me Me 45204-205 (AcOEt) 10 Me Me H 43 228-229 (AcOEt) 11 Me Me Me 49 205-206(AcOEt) 12 (CH₂)₄ H 52 196-197 (AcOEt)

Reference Example 13

Synthesis of(2-oxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetic acid

A solution of (6-hydroxy-2,3-dihydro-1H-inden-5-yl)(phenyl)methanone(1.0 g) and triethylamine (0.98 ml) in THF (20 ml) was combined withethyl succinyl chloride (0.55 ml) at 0° C., and stirred for 1 hour. Thereaction solution was combined with water, and the product was extractedwith ethyl acetate. The extract was washed with a 1 N solution ofhydrochloric acid followed by a saturated aqueous solution of sodiumchloride. After drying over magnesium sulfate, the solvent was distilledoff under reduced pressure. The resultant residue was dissolved intoluene (10 ml), combined with DBU (0.25 ml), and heated under refluxfor 2.5 hours. After cooling, the reaction solution was diluted withethyl acetate (60 ml), and washed with water followed by a 1 N solutionof hydrochloric acid and a saturated aqueous solution of sodiumchloride. After drying over magnesium sulfate, the solvent was distilledoff under reduced pressure, and the residue was purified by a columnchromatography (packing: silica gel, eluent: ethyl acetate-hexane=1:2).The resultant crude product of ethyl(2-oxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetate wasdissolved in acetic acid (20 ml) and concentrated hydrochloric acid (10ml), and heated under reflux for 1 hour. The reaction solution wasconcentrated under reduced pressure, and the resultant residue wasdissolved in a solvent mixture of THF (5 ml) and ethyl acetate (50 ml),and then washed with water followed by a saturated aqueous solution ofsodium hydrogen carbonate and a saturated aqueous solution of sodiumchloride. After drying over magnesium sulfate, the solvent was distilledoff under reduced pressure, and the residue was purified byrecrystallization from ethyl acetate-isopropyl ether to obtain the titlecompound (0.95 g, yield: 70%).

Melting point: 216-218° C.

NMR (CDCl₃) δ: 2.09 (2H, m), 2.81 (2H, d, J=7 Hz), 2.99 (2H, d, J=7 Hz),3.41 (2H, s), 6.82 (1H, s), 7.20-7.30 (3H, m), 7.50-7.60 (3H, m).

IR(KBr): 3400-2400, 1714, 1622 cm⁻¹.

Analysis for C₂₀H₁₆O₄ Calcd (%): C:74.99 H:5.03 Found (%): C:74.75H:5.13.

Reference Example 14-20

The compounds of table 3 were obtained by the method similar to that inReference Example 13.

TABLE 3

Melting Point (° C.) Ref.Ex. Yield (Recrystallization number R¹ R² R³ R⁴(%) solvent) 14 Cl Cl Cl H 13 244-246 (AcOEt) 15 F F H H 64 164-166(IPE) 16 Me Cl H H 65 222-224 (AcOEt) 17 (CH₂)₃ H 3-Me 63 183-184(AcOEt) 18 (CH₂)₃ H 4-Me 81 231-233 (AcOEt) 19 (CH₂)₃ H 3,4-di-Me 70193-194 (AcOEt) 20 (CH₂)₃ H 4-F 86 231-234 (AcOEt)

Reference Example 21

Synthesis of Ethyl2-(7-chloro-6-methyl-2-oxo-4-phenyl-2H-chromen-3-yl)acetate

A solution of (4-chloro-2-hydroxy-5-methylphenyl)(phenyl)methanone (5.0g) and triethylamine (5.65 ml) in THF (100 ml) was combined with ethylsuccinyl chloride (3.47 ml) at 0° C., and stirred for 1 hour. Thereaction solution was combined with water, and the product was extractedwith ethyl acetate. The extract was washed with a 1 N solution ofhydrochloric acid followed by a saturated aqueous solution of sodiumchloride, and after drying over magnesium sulfate, the solvent wasdistilled off under reduced pressure. The resultant residue wasdissolved in toluene (50 ml), combined with DBU (1.25 ml), and heatedunder reflux for 2.5 hours. After cooling, the reaction solution wasdiluted with ethyl acetate (100 ml), and washed with water followed by a1 N solution of hydrochloric acid and a saturated aqueous solution ofsodium chloride. After drying over magnesium sulfate, the solvent wasdistilled off under reduced pressure, and the residue was purified by acolumn chromatography (packing: silica gel, eluent: ethylacetate-hexane=1:4) and further purified by recrystallization from ethylacetate-hexane to obtain the title compound (3.86 g, yield: 53%).

Melting point: 132-133° C.

NMR (CDCl₃) δ: 1.23 (3H, t, J=7 Hz), 2.28 (2H, s), 3.36 (2H, s), 4.13(2H, t, J=7 Hz), 6.84 (1H, s), 7.20-7.35 (2H, m), 7.41 (1H, s),7.45-7.60 (3H, m).

IR(KBr): 1728, 1609, 1366, 1188 cm⁻¹.

Analysis for C₂₁H₁₇ClO₄ Calcd (%): C:67.32H:4.80 Found (%):C:67.55H:5.13.

Reference Example 22-23

The compounds of table 4 were obtained by the method similar to that inReference Example 21.

TABLE 4

Ref.Ex. Yield Melting Point (° C.) number R¹ R² (%) (Recrystallizationsolvent) 22 Me H 78 91-92 (Hexane) 23 Cl Me 71 oil

Reference Example 24

Synthesis of2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]acetic acid

A solution ofethyl(7-chloro-6-methyl-2-oxo-4-phenyl-2H-chromen-3-yl)acetate (3.5 g)in ethyl acetate (50 ml) was combined with N-bromosuccinimide (2.1 g)and 2,2′-azoisobutyronitrile (48.3 mg), and heated under reflux for 1hour. After cooling, the reaction solution was washed with waterfollowed by a saturated aqueous solution of sodium hydrogen carbonateand a saturated aqueous solution of sodium chloride. After drying overmagnesium sulfate, the solvent was distilled off under reduced pressure,and the residue was purified by a silica gel column chromatography(eluent: ethyl acetate-hexane=1:4) to obtain the crude crystal(approximately 2.6 g) of ethyl2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]acetate. Thecrude crystal was dissolved in acetic acid (50 ml) and concentratedhydrochloric acid (25 ml), and heated under reflux for 30 minutes. Thereaction solution was concentrated under reduced pressure, and theresultant residue was dissolved in a solvent mixture of THF (10 ml) andethyl acetate (50 ml), and then washed with water followed by asaturated aqueous solution of sodium hydrogen carbonate and a saturatedaqueous solution of sodium chloride. After drying over magnesiumsulfate, the solvent was distilled off under reduced pressure, and theresidue was washed with ethyl acetate to obtain a crude crystal (1.78 g,yield: 44%) of the title compound. The compound was used in the nextreaction without further purification. NMR (CDCl₃) δ: 3.43 (2H, s), 4.58(2H, s), 7.11 (1H, s), 7.20-7.30 (2H, m), 7.48 (1H, s), 7.50-7.65 (3H,m).

Reference Example 25-26

The compounds of table 5 were obtained by the method similar to that inReference Example 24.

TABLE 5

Ref.Ex. Yield NMR number R¹ R² (%) (CDCl₃) 25 CH₂Br H 50 3.44 (2H, s),4.49 (2H, s), 7.03 (1H, d, J=2H), 7.20-7.35 (1H, m), 7.41 (1H, d, J=8Hz), 7.50-7.65 (5H, m). 26 Cl CH₂Br 43 3.44 (2H, s), 4.71 (2H, s), 7.06(1H, s), 7.20-7.70 (6H, m).

Reference Example 27

Synthesis ofethyl(2,8-oxo-4-phenyl-2,6,7,8-tetrahydroxycyclopenta[g]chromen-3-yl)acetate

A suspension of chromium oxide (33 g) in methylene chloride (300 ml) wascombined with 3,5-dimethylpyrazole (32 g) at −10° C. in one portion.After stirring at the same temperature for 15 minutes,ethyl(2-oxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetatewas added. After the reaction solution was stirred at −10° C. for 2hours, and combined with water, and the organic layer was washed withdiluted hydrochloric acid and water, and dried over magnesium sulfate.The solvent was distilled off under reduced pressure, the resultantresidue was purified by a silica gel column chromatography (eluent:ethyl acetate), and further purified by recrystallization from ethylacetate to obtain the title compound (1.2 g, yield: 15%).

Melting point: 145-148° C.

NMR (CDCl₃) δ: 1.23 (3H, t, J=9 Hz), 2.75 (2H, t, J=6 Hz), 3.08 (2H, t,J=6 Hz), 3.41 (2H, s), 4.14 (2H, q, J=9 Hz), 7.10 (1H, s), 7.28 (2H, m),7.55 (3H, m), 7.71 (1H, s).

IR(KBr): 2980, 1715, 1615, 1563 cm⁻¹.

Analysis for C₂₂H₁₈O₅ Calcd (%): C:72.92H:5.01 Found (%): C:73.15H:5.20

Reference Example 28

Synthesis of(2,8-dioxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)aceticacid

Ethyl(2,8-dioxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetate(1.2 g) was dissolved in acetic acid (20 ml) and concentratedhydrochloric acid (10 ml), and heated under reflux for 30 minutes. Thereaction solution was concentrated under reduced pressure, and theresultant residue was dissolved in a solvent mixture of THF (10 ml) andethyl acetate (50 ml), and then washed with water followed by asaturated aqueous solution of sodium hydrogen carbonate and a saturatedaqueous solution of sodium chloride. After drying over magnesiumsulfate, the solvent was distilled off under reduced pressure, and theresidue was purified by recrystallization from ethyl acetate to obtainthe title compound (0.87 g, yield: 79%).

Melting point: 240° C. (decomp.).

NMR (CDCl₃+DMSO-d₆ 1 drop) δ: 2.74 (2H, t, J=6 Hz), 3.08 (2H, t, J=6Hz), 3.40 (2H, s), 7.11 (1H, s), 7.32 (2H, m), 7.56 (3H, m), 7.68 (1H,s)

IR(KBr): 3400-2400, 1713 cm⁻¹.

Analysis for C₂₀H₁₄O₅ Calcd (%): C:71.85H:4.22 Found (%): C:71.40H:4.50.

Example 1

Synthesis ofN-(2,6-dimethoxyphenyl)-2-(2-oxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetamide

A solution of(2-oxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetic acid(150 mg) in THF (10 ml) was combined with dimethylformamide (DMF, 1drop) and oxalyl chloride (0.06 ml), and stirred at room temperature for30 minutes. The reaction solution was concentrated under reducedpressure, and the resultant residue was dissolved in THF (10 ml), andadded dropwise to a solution of 2,6-dimethoxyaniline (79 mg) andtriethylamine (0.1 ml) in THF (5 ml). After stirring at room temperaturefor 1 hour, the solvent was distilled off under reduced pressure, andthe resultant residue was combined with water, and extracted with ethylacetate. The extract was washed with diluted hydrochloric acid followedby a 1 N solution of sodium hydroxide and water, dried over magnesiumsulfate, and then concentrated. The resultant residue was purified byrecrystallization from ethyl acetate-THF to obtain the title compound(146 mg, yield: 64%).

Melting point: 213-215° C.

NMR (CDCl₃) δ: 2.09 (2H, m), 2.81 (2H, t, J=7 Hz), 2.99 (2H, t, J=7 Hz),3.46 (2H, br) 3.78 (6H, s), 6.54 (2H, d, J=8 Hz), 6.85 (1H, s), 7.14(1H, t, J=8 Hz), 7.26 (1H, s), 7.43 (2H, m), 7.50 (1H, m).

IR(KBr): 1707, 1686, 1508 cm⁻¹.

Analysis for C₂₈H₂₅NO₅.0.2H₂O Calcd (%): C:73.25H:5.58 N:3.05 Found (%):C:73.04H:5.79 N:3.14.

Example 2-14

The compounds of table 6 were obtained using(2-oxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetic acidby the method similar to that in Example 1.

TABLE 6

Example Yield Melting Point (° C.) number R¹ R² R³ (%)(Recrystallization solvent) 2 OEt OEt H 64 216-219 AcOEt-THF) 3 CH(CH₃)₂CH(CH₃)₂ H 40 261-263 (AcOEt-THF) 4 Et Et H 54 279-281 (AcOEt-THF) 5 MeOMe H 42 232-237 (AcOEt) 6 Et H H 46 234-237 (AcOEt-THF) 7 OMe H H 40219-222 (AcOEt-THF) 8 OMe OMe Me 73 237-239 (AcOEt-THF) 9 OMe OH H 72179-181 (AcOEt) 10 OMe OMe OH 40 160 (decomp.) (AcOEt) 11 OH OMe OMe 32170-172 (AcOE) 12 OCF₃ H H 21 191-194 (AcOEt) 13 OCH(CH₃)₂ OCH(CH₃)₂ H33 181-186 (AcOEt) 14 cyclopentyloxy cyclopentyloxy H 47 224-226 (AcOEt)

Example 15

Synthesis ofN-(3,5-dichloro-4-pyridyl)-2-(2-oxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetamide

A solution of(2-oxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetic acid(150 mg) in THF (10 ml) was combined with DMF (1 drop), and the mixturesolution was combined with oxalyl chloride (0.06 ml), and stirred atroom temperature for 30 minutes. The reaction solution was concentratedunder reduced pressure, and the resultant residue was dissolved in THF(10 ml), and added dropwise to a suspension of4-amino-3,5-dichloropyridine (100 mg) and sodium hydride (60%, in oil)(40 mg) in THF. After stirring at room temperature overnight, thereaction solution was combined with water, and extracted with ethylacetate. The extract was washed with water, dried over magnesiumsulfate, and then concentrated. The resultant residue was purified byrecrystallization from ethyl acetate-THF to obtain the title compound asa colorless crystal (60 mg, 28%).

Melting point: 257-259° C.

NMR (CDCl₃) δ: 2.11 (2H, m), 2.27 (3H, m), 2.90 (2H, t, J=7 Hz), 2.99(2H, t, J=7 Hz), 3.71 (6H, s), 6.54 (1H, s), 6,56 (2H, d, J=8 Hz), 6.86(1H, bs), 7.06 (1H, s), 7.15 (1H, t, J=8 Hz), 7.33 (5H, m).

IR(KBr): 1699, 1655, 1306, 1144 cm⁻¹.

Analysis for C₂₅H₁₈N₂O₃Cl₂.0.3H₂O Calcd (%): C:63.79H:3.98 N:5.95 Found(%): C:63.56H:4.10 N:5.71.

Example 16-21

The compounds of table 7 were obtained using(2-oxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta [g] chromen-3-yl) aceticacid by the method similar to that in Example 15.

TABLE 7

Example Yield Melting Point (° C.) number R¹ R² R³ (%)(Recrystallization solvent) 16 CF₃ H Cl 55 198-200 (AcOEt) 17 F F F 46247-249 (THF-IPE) 18 CF₃ F H 19 194-196 (AcOEt) 19 OCF₃ H Cl 84 189-191(AcOEt) 20 CF₃ H F 57 186-187 (AcOEt) 21 CF₃ H CF₃ 38 220-221 (AcOEt)

Example 22-46

The compounds of table 8 to table 11 were obtained by the method similarto that in Example 1.

TABLE 8

Melting Point (° C.) Example Yield (Recrystallization number R¹ R² R³(%) solvent) 22 OMe OMe H 57 231-232 (AcOEt) 23 OMe OMe Me 61 176-177(AcOEt) 24 OEt OEt H 54 235-236 (AcOEt) 25 CH(CH₃)₂ CH(CH₃)₂ Cl 51245-246 (AcOEt) 26 Et Et H 53 250-251 (AcOEt)

TABLE 9

Melting Point (° C.) Example Yield (Recrystallization number R¹ R² R³ R⁴(%) solvent) 27 Me Me OMe H 75 236-237 (AcOEt) 28 Me Me OMe Me 74166-167 (AcOEt) 29 Me Me OEt H 75 230-231 (AcOEt) 30 Me Me Et H 74259-260 (AcOEt) 31 Me Me CH(CH₃)₂ H 74 252-253 (AcOEt) 32 (CH₂)₄ OMe H63 227-228 (AcOEt) 33 (CH₂)₄ OEt H 60 196-197 (AcOEt) 34 (CH₂)₄ CH(CH₃)₂H 53 235-236 (AcOEt) 35 (CH₂)₄ Et H 55 240-241 (AcOEt)

TABLE 10

Melting Point (° C.) Example Yield (Recrystallization number R¹ R² R³(%) solvent) 36 Cl H OMe 48 249-250 (AcOEt) 37 Cl H OEt 55 246-247(AcOEt) 38 Cl H Et 48 296-297 (AcOEt) 39 Cl H CH(CH₃)₂ 55 289-290(AcOEt) 40 Cl Cl OMe 83 289-291 (THF) 41 F H OMe 73 196-198 (AcOEt-THF)42 F H CH(CH₃)₂ 75 255-256 (AcOEt-THF) 43 F H OCH(CH₂)₃ 55 249-252(AcOEt) 44 F H cyclopentyloxy 38 253-254 (AcOEt)

TABLE 11

Example Yield Melting Point (° C.) number R¹ (%) (Recrystallizationsolvent) 45 OMe 60 247-249 (THF) 46 CH(CH₃)₂ 42 280-282 (THF)

Example 47-69

The compounds of table 12 were obtained by the method similar to that inExample 15.

TABLE 12

Example Yield Melting Point (° C.) number R¹ R² R³ R⁴ (%)(Recrystallization solvent) 47 F F H 2-CF₃, 4-Cl 55 172-174 (AcOEt) 48Cl Cl H 2-CF₃, 4-Cl 61 203-206 (AcOEt) 49 Me Cl H 2-CF₃, 4-Cl 74 236-239(AcOEt-IPE) 50 Me Cl H 2-CF₃, 4-F 78 224-226 (AcOEt-IPE) 51 Me Cl H2,4-di-(CF₃) 51 239-240 (AcOEt-IPE) 52 Me Cl H 2-OCF₃, 4-Cl 37 214-215(AcOEt-IPE) 53 Me Cl 3-Cl 2-CF₃, 4-Cl 51 202-204 (AcOEt-IPE) 54 Me Me H2-CF₃, 4-Cl 65 201-203 (AcOEt) 55 Cl Me H 2-CF₃, 4-Cl 93 214-216 (AcOEt)56 (CH₂)₃ H 2-CF₃ 79 191-193 (AcOEt) 57 (CH₂)₃ 3-Me 2-CF₃ 68 205-207(AcOEt) 58 (CH₂)₃ 3-Me 2-CF₃, 4-F 77 204-205 (AcOEt) 59 (CH₂)₃ 3-Me2-CF₃, 4-Cl 59 182-184 (AcOEt) 60 (CH₂)₃ 4-Me 2-CF₃ 64 224-226 (AcOEt)61 (CH₂)₃ 4-Me 2-CF₃, 4-F 68 234-236 (AcOEt) 62 (CH₂)₃ 4-Me 2-CF₃, 4-Cl61 235-236 (AcOEt) 63 (CH₂)₃ 3,5-di-Me 2-CF₃ 81 264-265 (AcOEt) 64(CH₂)₃ 3,5-di-Me 2-CF₃, 4-F 72 226-228 (AcOEt) 65 (CH₂)₃ 3,5-di-Me2-CF₃, 4-Cl 78 221-223 (AcOEt) 66 (CH₂)₃ 4-F 2-CF₃ 74 221-223 (AcOEt) 67(CH₂)₃ 4-F 2-CF₃, 4-F 88 234-236 (AcOEt) 68 (CH₂)₃ 4-F 2-CF₃, 4-Cl 71232-234 (AcOEt) 69 Me Cl H 2-CF₃ 63 224-225 (AcOEt-IPE)

Example 70

Synthesis of2-[7-chloro-6-{(dimethylamino)methyl}-2-oxo-4-phenyl-2H-chromen-3-yl]-N-(2,6-dimethoxyphenyl)acetamide

A solution of2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]acetic acid(0.13 g) in THF (3 ml) was combined with DMF (1 drop) and oxalylchloride (56 ml), and stirred at room temperature for 1 hour. Thereaction solution was concentrated under reduced pressure, and theresultant residue was dissolved in THF (2 ml), and added dropwise to asolution of 2,6-dimethoxyaniline (46 ml) and triethylamine (86 ml) inTHF (2 ml) at 0° C. After stirring for 1 hour, the reaction solution wascombined with water, and the solution was extracted with ethyl acetate.The extract was washed with a 1 N solution of hydrochloric acid followedby a saturated aqueous solution of sodium chloride, a saturated aqueoussolution of sodium hydrogen carbonate and a saturated aqueous solutionof sodium chloride, and after drying over magnesium sulfate, the solventwas distilled off under reduced pressure. The resultant residue wasdissolved in THF (2 ml), combined with a solution of dimethylamine (200mg) in THF (1 ml), and stirred overnight. The reaction solution wasconcentrated under reduced pressure, and the resultant residue wasdissolved in ethyl acetate (30 ml), and then washed with a saturatedaqueous solution of sodium chloride. After drying over magnesiumsulfate, the solvent was distilled off under reduced pressure. Theresultant residue was purified by a silica gel column chromatography(eluent: chloroform-methanol-aqueous ammonia=30:1:0.1), and furtherpurified by recrystallization from ethyl acetate to obtain the titlecompound (81 mg, yield: 50%).

Melting point: 221-223° C.

NMR (CDCl₃) δ: 2.17 (6H, s), 3.41 (2H, s), 3.48 (2H, brs), 3.79 (6H,brs), 6.54 (2H, d, J=8 Hz), 7.08 (1H, brs), 7.15 (1H, t, J=8 Hz),7.35-7.60 (8H, m).

IR(KBr): 1732, 1661, 1560, 1478 cm⁻¹.

Analysis for C₂₈H₂₇N₂O₅Cl Calcd (%): C:66.33H:5.37 N:5.53 Found (%):C:66.17H:5.38 N:5.22.

Example 71-73

The compounds of table 13 were obtained by the method similar to that inExample 70.

TABLE 13

Melting Point (° C.) Example Yield (Recrystallization number R¹ R² (%)solvent) 71 morpholin-4-yl OMe 53 209-211 (AcOEt) 72 NMe₂ CH(CH₃)₂ 54301-303 (AcOEt) 73 morpholin-4-yl CH(CH₃)₂ 53 296-298 (AcOEt)

Example 74

Synthesis of2-[7-chloro-6-{(morpholin-4-yl)methyl}-2-oxo-4-phenyl-2H-chromen-3-yl]-N-(4-chloro-2-trifluoromethylphenyl)acetamide

A solution of2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]acetic acid(0.20 g) in THF (5 ml) was combined with DMF (1 drop) and oxalylchloride (86 ml), and stirred at room temperature for 1 hour. Thereaction solution was concentrated under reduced pressure to obtain theresidue, which was dissolved in THF (3 ml), and added dropwise to asuspension of 4-chloro-2-trifluoromethylaniline (69 ml) and sodiumhydride (60%, in oil) in THF (2 ml) at 0° C. After stirring at roomtemperature for 12 hours, the reaction solution was combined with water,and the product was extracted with ethyl acetate. The extract was washedwith a 1 N solution of hydrochloric acid followed by a saturated aqueoussolution of sodium chloride, a saturated aqueous solution of sodiumhydrogen carbonate and a saturated aqueous solution of sodium chloride,and after drying over magnesium sulfate, the solvent was distilled offunder reduced pressure. The resultant residue was dissolved in THF (2ml), combined with morpholine (0.21 ml), and stirred for 3 days. Thereaction solution was concentrated under reduced pressure, and theresultant residue was dissolved in ethyl acetate (30 ml), and thenwashed with a saturated aqueous solution of sodium chloride. Afterdrying over magnesium sulfate, the solvent was distilled off underreduced pressure. The resultant residue was purified by a silica gelcolumn chromatography (eluent: chloroform-methanol-aqueousammonia=40:1:0.1), and further purified by recrystallization from ethylacetate to obtain the title compound (112 mg, yield: 57%).

Melting point: 205-207° C.

NMR (CDCl₃) δ: 2.35-2.45 (4H, m), 3.45-3.65 (8H, m), 7.21 (1H, s),7.30-7.40 (2H, m), 7.45 (1H, s), 7.45-7.65 (5H, m), 8.08 (1H, d, J=9Hz), 8.24 (1H, brs).

IR(KBr): 1725, 1663, 1530, 1310 cm⁻¹.

Analysis for C₂₉H₂₃N₂O₄Cl₂F₃ Calcd (%): C:58.90H:3.92 N:4.74 Found (%):C:58.90H:3.89 N:4.61.

Example 75-79

The compounds of table 14 were obtained by the method similar to that inExample 74.

TABLE 14

Melting Point (° C.) Example Yield (Recrystallization number R¹ R² (%)solvent) 75 4-phenyl-1- Cl 74 201-203 (AcOEt-IPE) piperazinyl methyl 76CH₂NMe₂ H 35 176-178 (AcOEt-IPE) 77 morpholin-4- H 36 171-172 (AcOE-IPE)ylmethyl 78 Cl CH₂NMe₂ 95 215-217 (AcOEt-IPE) 79 Cl morpholin-4- 69216-218 (AcOEt-IPE) ylmethtyl

Example 80

Synthesis of[7-chloro-3-{2-(2,6-dimethoxyanilino)-2-oxoethyl}-2-oxo-4-phenyl-2H-chromen-6-yl]methylacetate

A solution of2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]acetic acid(0.13 g) in THF (3 ml) was combined with DMF (1 drop) and oxalylchloride (56 ml), and stirred at room temperature for 1 hour. Thereaction solution was concentrated under reduced pressure, and theresultant residue was dissolved in THF (2 ml), and added dropwise to asolution of 2,6-dimethoxyaniline (46 ml) and triethylamine (86 ml) inTHF (2 ml) at 0° C. After stirring for 1 hour, the reaction solution wascombined with water, and the product was extracted with ethyl acetate.The extract was washed with a 1 N solution of hydrochloric acid followedby a saturated aqueous solution of sodium chloride, a saturated aqueoussolution of sodium hydrogen carbonate and a saturated aqueous solutionof sodium chloride, and after drying over magnesium sulfate, the solventwas distilled off under reduced pressure. The resultant residue wasdissolved in DMF (2 ml), combined with anhydrous sodium acetate (150mg), and stirred at 60° C. for 3 hours. The reaction solution wascombined with water, and the product was extracted with ethyl acetate,and the extract was washed with a saturated aqueous solution of sodiumchloride. After drying over magnesium sulfate, the solvent was distilledoff under reduced pressure, and the resultant residue was purified byrecrystallization from THF to obtain the title compound (61 mg, yield:36%).

Melting point: 229-231° C.

NMR (CDCl₃) δ: 1.99 (3H, s), 3.50 (2H, brs), 3.78 (6H, brs), 5.09 (2H,s), 6.55 (2H, d, J=8 Hz), 7.06 (1H, brs), 7.16 (1H, t, J=8 Hz),7.25-7.60 (8H, m).

IR(KBr): 1737, 1732, 1477, 1260 cm⁻¹.

Analysis for C₂₈H₂₄NO₇Cl Calcd (%): C:64.43H:4.63 N:2.68 Found (%):C:64.45H:4.95 N:2.64.

Example 81

Synthesis of[7-chloro-3-{2-(2,6-isopropylanilino)-2-oxoethyl}-2-oxo-4-phenyl-2H-chromen-6-yl]]methylacetate

The title compound (yield: 27%) was obtained by the method similar tothat in Example 80.

Melting point: 290-292° C.

NMR (CDCl₃) δ: 1.15 (12H, d, J=7 Hz), 1.99 (3H, s), 3.03 (2H, m), 3.53(2H, s), 5.10 (2H, s), 7.00-7.60 (1H, m).

IR(KBr): 1732, 1647, 1532, 1364 cm⁻¹.

Analysis for C₃₂H₃₂NO₅Cl Calcd (%): C:70.39H:5.91 N:2.57 Found (%):C:70.41H:5.67 N:2.58.

Example 82

Synthesis of[7-chloro-3-{2-(4-chloro-2-trifluoromethylanilino)-2-oxoethyl}-2-oxo-4-phenyl-2H-chromen-6-yl]methylacetate

A solution of2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]acetic acid(0.30 g) in THF (6 ml) was combined with DMF (1 drop) and oxalylchloride (130 ml), and stirred at room temperature for 1 hour. Thereaction solution was concentrated under reduced pressure to obtain theresidue, which was dissolved in THF (3 ml), and added dropwise to asuspension of 4-chloro-2-fluoromethylaniline (104 ml) and sodium hydride(60%, in oil)(121 mg) in THF (2 ml) at 0° C. After stirring for 1 hour,the reaction solution was combined with water, and the product wasextracted with ethyl acetate. The extract was washed with a 1 N solutionof hydrochloric acid followed by a saturated aqueous solution of sodiumchloride, a saturated aqueous solution of sodium hydrogen carbonate anda saturated aqueous solution of sodium chloride, and after drying overmagnesium sulfate, the solvent was distilled off under reduced pressure.The resultant residue was dissolved in DMF (3 ml), combined withanhydrous sodium acetate (121 mg), and stirred at 60° C. for 3 hours.The reaction solution was combined with water, and the product wasextracted with ethyl acetate, and the extract was washed with asaturated aqueous solution of sodium chloride. After drying overmagnesium sulfate, the solvent was distilled off under reduced pressureto obtain the residue, which was purified by a silica gel columnchromatography (eluent: ethyl acetate-hexane=1:2), and further purifiedby recrystallization from ethyl acetate to obtain the title compound(126 mg, yield: 45%).

Melting point: 186-187° C.

NMR (CDCl₃) δ: 1.99 (3H, s), 3.49 (2H, s), 5.10 (2H, s), 7.08 (1H, s),7.30-7.40 (2H, m), 7.45-7.65 (6H, m), 8.08 (1H, d, J=9 Hz), 8.17 (1H,brs).

IR(KBr): 1725, 1663, 1530, 1310 cm⁻¹.

Analysis for C₂₇H₁₈NO₅Cl₂F₃ Calcd (%): C:57.46H:3.21 N:2.48 Found (%):C:57.20H:3.25 N:2.25

Example 83-84

The compounds of table 15 were obtained by the method similar to that inExample 82.

TABLE 15

Example Yield Melting Point (° C.) number R¹ R² (%) (Recrystallizationsolvent) 83 CH₂OAc H 35 184-185 (AcOEt) 84 Cl CH₂OAc 56 237-238(AcOEt-IPE)

Example 85

Synthesis of2-[7-chloro-6-{(hydroxylmethyl)-2-oxo-4-phenyl-2H-chromen-3-yl)-N-(4-chloro-2-trifluoromethylphenyl)acetamide

[7-chloro-3-{2-(4-chloro-2-trifluoromethylanilino)-2-oxoethyl)-2-oxo-4-phenyl-2H-chromen-6-yl)methyl acetate ester (81 mg) was dissolved in a solvent mixture of THF(4 ml) and methanol (2 ml), combined with DBU (0.11 ml), and stirred atroom temperature for 30 minutes. The reaction solution was diluted withethyl acetate (30 ml), and then washed with a 1 N solution ofhydrochloric acid followed by a saturated aqueous solution of sodiumchloride, a saturated aqueous solution of sodium hydrogen carbonate anda saturated aqueous solution of sodium chloride, and after drying overmagnesium sulfate, the solvent was distilled off under reduced pressure.The resultant residue was purified by a silica gel column chromatography(eluent: ethyl acetate), and further purified by recrystallization fromethyl acetate to obtain the title compound (34 mg, yield: 80%).

Melting point: 241-243° C.

NMR (CDCl₃) δ: 1.85 (1H, t, J=6 Hz), 3.48 (2H, s), 4.70 (2H, d, J=6 Hz),7.21 (1H, s), 7.30-7.40 (2H, m), 7.45-7.65 (6H, m), 8.08 (1H, d, J=9Hz), 8.19 (1H, brs).

IR(KBr): 1699, 1655, 1306, 1144 cm⁻¹.

Analysis for C₂₅H₁₆NO₄Cl₂F₃ Calcd (%): C:57.49H:3.09 N:2.68 Found (%):C:57.52H:3.09 N:2.57.

Example 86-87

The compounds of table 16 were obtained by the method similar to that inExample 85.

TABLE 16

Example Yield Melting Point (° C.) number R¹ R² (%) (Recrystallizationsolvent) 86 CH₂OH H 37 226-227 (AcOEt) 87 Cl CH₂OH 46 220-222(AcOEt-IPE)

Example 88-89

The compounds of table 17 were obtained by the method similar to that inExample 15.

TABLE 17

Example Yield Melting Point (° C.) number R (%) (Recrystallizationsolvent) 88 F 52 180-183 (AcOEt) 89 Cl 33 189-192 (THF-IPE)

Reference Example 29-31

The compounds of table 18 were obtained by the method similar to that inReference Example 7.

TABLE 18

Ref.Ex. Yield Melting Point (° C.) number R (%) (Recrystallizationsolvent) 29 3-CF₃ 82 159-161 (Et₂O-hexane) 30 4-CF₃ 82 202-204 (IPE) 313,5-di-(CF₃) 75 193-195 (IPE-hexane)

Reference Example 32-34

The compounds of table 19 were obtained by the method similar to that inReference Example 27.

TABLE 19

Ref.Ex. Yield Melting Point (° C.) number R (%) (Recrystallizationsolvent) 32 3,5-di-Me 16 174-276 (AcOEt) 33 3-Me 12 182-184 (AcOEt) 343-CF₃ 22 142-143 (Et₂O-hexane)

Reference Example 35-37

The compounds of table 20 were obtained by the method similar to that inReference Example 28.

TABLE 20

Ref. Ex. Yield Melting Point (° C.) number R (%) (Recrystallizationsolvent) 35 3,5-di-Me 70 187-190 (AcOEt) 36 3-Me 89 247 (decomp.)(AcOEt) 37 3-CF₃ 90 200-202 (Et₂O-IPE)

Example 90-95

The compounds of table 21 were obtained by the method similar to that inExample 15.

TABLE 21

Example Yield Melting Point (° C.) number R¹ R² (%) (Recrystallizationsolvent) 90 F 3-CF₃ 58 213-214 (AcOEt-IPE) 91 Cl 3-CF₃ 70 206-207(THF-IPE) 92 F 4-CF₃ 78 250-252 (THF-IPE) 93 Cl 4-CF₃ 55 249-250 (AcOEt)94 F 3,5-di-(CF₃) 58 278-280 (THF-IPE) 95 Cl 3,5-di-(CF₃) 70 254-256(THF-IPE)

Example 96-101

The compounds of table 22 were obtained by the method similar to that inExample 15.

TABLE 22

Example Yield Melting Point (° C.) number R¹ R² (%) (Recrystallizationsolvent) 96 F 3,5-di-Me 19 274-276 (AcOEt-IPE) 97 Cl 3,5-di-Me 12274-276 (THF-IPE) 98 F 3-Me 49 216-217 (AcOEt) 99 Cl 3-Me 60 225-227(AcOEt-IPE) 100 F 3-CF₃ 19 227-229 (AcOEt-IPE) 101 Cl 3-CF₃ 43 122-123(AcOEt-hexane)

Reference Example 38

Synthesis of3-(2-methylphenyl)-6,7-dihydro-5H-indeno[5,6-b]furan-2-carboxylic acid

A solution of(6-hydroxy-2,3-dihydro-1H-inden-5-yl)(2-methylphenyl)methanone (2.0 g)in DMF (50 ml) was combined with sodium hydride (60%, in oil) (400 mg)with cooling in ice. After stirring at the same temperature for 30minutes, the mixture was combined with ethyl bromoacetate (1 ml), andstirred for 1 hour. The reaction solution was combined with water andextracted with ethyl acetate. The extract was washed with water, andthen dried over magnesium sulfate, and the solvent was distilled offunder reduced pressure. The resultant residue was dissolved in toluene(50 ml), and combined with DBU (2 ml). The reaction solution was heatedunder reflux overnight, and then combined with water, and extracted withethyl acetate. The extract was washed with water, and then dried overmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resultant residue was purified by a column chromatography(packing: silica gel, eluent: ethyl acetate-hexane=1:3) to obtain acrude product of ethyl3-(2-methylphenyl)-6,7-dihydro-5H-indeno[5,6-b]furan-2-carboxylate. Theresultant crude product of ester was dissolved in a solvent mixture ofTHF (50 ml) and methanol (30 ml), combined with a 1 N solution of sodiumhydroxide (30 ml), and stirred at room temperature for 3 hours. Thereaction solution was concentrated under reduced pressure, and theresultant residue was combined with water and extracted with ethylacetate after acidifying with diluted hydrochloric acid. The extract waswashed with water, and then dried over magnesium, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby recrystallization from ethyl acetate to obtain the title compound(0.9 g, yield: 39%) as a colorless crystal.

Melting point: 213-215° C.

NMR (CDCl₃) δ: 2.13 (2H, m), 2.17 (3H, m), 2.91 (2H, t, J=8 Hz), 3.04(2H, t, J=8 Hz), 7.11 (1H, s), 7.26 (2H, m), 7.32 (2H, m), 7.45 (1H, s).

IR(KBr): 3400-2400, 1720 cm⁻¹.

Analysis for C₁₉H₁₆O₃

Calcd (%): C:78.06H:5.52

Found (%): C:77.82H:5.59.

Reference Example 39-53

The compounds of table 23 and table 24 were obtained by the methodsimilar to that in Reference Example 38.

TABLE 23

Ref.Ex. Yield Melting Point (° C.) number R (%) (Recrystallizationsolvent) 39 3-Me 72 240-244 (AcOEt) 40 4-Me 76 240-244 (AcOEt) 41 H 63230-231 (AcOEt) 42 4-F 48 215-218 (AcOEt) 43 4-OMe 85 240-243 (AcOEt)

TABLE 24

Ref. Ex. Yield Melting Point (° C.) number R¹ R² R³ (%)(Recrystallization solvent) 44 2-Me Cl Me 53 224-225 (AcOEt) 45 H Me Me46 268-269 (AcOEt) 46 2-Me Me Me 39 218-219 (AcOEt) 47 3-Me Me Me 62224-226 (AcOEt) 48 2-Me Me Cl 78 190-220 (AcOEt) 49 3-Me Me Cl 33210-213 (AcOEt) 50 2-Me Cl Cl 62 193-195 (AcOEt-hexane) 51 2-Me F F 40206-208 (AcOEt) 52 2-Me (CH₂)₄ 86 Amorphous 53 3-Me (CH₂)₄ 34 228-230(AcOEt)

Example 102

N-(2,6-Dimethoxyphenyl)-N′-[3-(2-methylphenyl)-6,7-dihydro-5H-indeno[5,6-b]furan-2-yl]urea

A solution of3-(2-methylphenyl)-6,7-dihydro-5H-indeno[5,6-b]furan-2-carboxylic acid(3 g), triethylamine (2.2 ml) and DPPA (2.9 ml) in benzene (200 ml) wasstirred at room temperature for 1 hour, and then heated under reflux for1 hour. After cooling to room temperature, to the reaction solution2,6-dimethoxyaniline (1.6 g) was added and then heated under reflux for1 hour. The reaction solution was combined with water and chloroform,and the organic layer was washed with diluted hydrochloric acid followedby a saturated aqueous solution of sodium hydrogen carbonate and water,and after drying over magnesium sulfate, the solvent was distilled offunder reduced pressure. The resultant residue was purified by a silicagel column chromatography (eluent: chloroform), and further purified byrecrystallization from THF-chloroform to obtain the title compound as acolorless crystal (2.4 g, 53%).

Melting point: 270° C. (decomp.).

NMR (CDCl₃) δ: 2.11 (2H, m), 2.27 (3H, m), 2.90 (2H, t, J=7 Hz), 2.99(2H, t, J=7 Hz), 3.71 (6H, s), 6.54 (1H, s), 6.56 (2H, d, J=8 Hz), 6.86(1 h, bs), 7.06 (1H, s), 7.15 (1H, t, J=8 Hz), 7.33 (5H, m).

IR(KBr): 3241, 1659, 1557 cm⁻¹.

Analysis for C₂₇H₂₆N₂O₄ Calcd (%): C:78.28H:5.92 N:6.33 Found (%):C:73.15H:6.00 N:6.29.

Example 102-103

The compounds of table 25 and table 26 were obtained by the methodsimilar to that in Example 101.

TABLE 25

Example Yield Melting Point (° C.) number R¹ R² R³ R⁴ (%)(Recrystallization solvent) 102 3-Me OMe OMe H 19 208 (decomp.) (AcOEt)103 4-Me OMe OMe H 53 236 (decomp.) (AcOEt) 104 H OMe OMe H 50 238-241(AcOEt) 105 2-Me Et Et H 28 250 (decomp.) (AcOEt) 106 3-Me Et Et H 23225-228 (AcOEt) 107 4-Me Et Et H 26 250-254 (AcOEt) 108 H Et Et H 42248-251 (AcOEt) 109 2-Me OEt OEt H 45 227 (decomp.) (AcOEt) 110 3-Me OEtOEt H 14 210-212 (AcOEt) 111 H OEt OEt H 45 210-212 (AcOEt) 112 2-MeCH(CH₃)₂ CH(CH₃)₂ H 33 238 (decomp.) (AcOEt) 113 3-Me CH(CH₃)₂ CH(CH₃)₂H 34 235 (decomp.) (AcOEt) 114 3-Me OMe Me H 19 208 (decomp.) (AcOEt)115 2-Me OMe OMe Me 69 280 (decomp.) (AcOEt-hex) 116 2-Me OMe OH H 78210-212 (THF) 117 2-Me OMe OMe OH 27 224-227 (AcOEt) 118 2-Me OMe OH OMe36 218-221 (AcOEt) 119 2-Me OMe OMe F 45 280 (decomp.) (CH₂Cl₂) 120 4-FOMe OMe H 36 246 (decomp.) (AcOEt) 121 4-OMe OMe OMe H 58 238 (decomp.)(AcOEt)

TABLE 26

Example Yield Melting Point (° C.) number R¹ R² R³ R⁴ (%)(Recrystallization solvent) 122 2-Me Cl Me OMe 35 282 (decomp.) (THF)123 H Me Me OMe 28 252 (decomp.) (THF) 124 2-Me Me Me OMe 39 238(decomp.) (AcOEt) 125 3-Me Me Me OMe 47 230 (decomp.) (AcOEt) 126 2-MeMe Cl OMe 34 242 (decomp.) (AcOEt) 127 3-Me Me Cl OMe 34 238 (decomp.)(AcOEt) 128 3-Me Me Cl Et 23 235-239 (AcOEt) 129 2-Me Cl Cl OMe 17275-277 (THF) 130 2-Me F F OMe 26 194-196 (THF) 131 2-Me (CH₂)₄ OMe 26195 (decomp.) (AcOEt) 132 3-Me (CH₂)₄ OMe 47 215 (decomp.) (AcOEt) 1333-Me (CH₂)₄ Et 32 235 (decomp.) (AcOEt)

Reference Example 54-63

The compounds of table 27 were obtained by the method similar to that inReference Example 13.

TABLE 27

Ref.Ex. Yield Melting Point (° C.) number R¹ R² R³ (%)(Recrystallization solvent) 54 (CH₂)₄ 3-Me 89 203-206 (AcOEt-IPE) 55 MeCl 3-Cl 58 262-264 (AcOEt-IPE) 56 (CH₂)₃ 3-Cl 63 210-213 (AcOEt-IPE) 57(CH₂)₄ 3-Cl 73 233-238 (AcOEt-IPE) 58 Me Cl 4-CF₃ 96 231-234(AcOEt-hexane) 59 (CH₂)₃ 3,4-Me₂ 87 189-191 (AcOEt) 60 (CH₂)₃ 3-Cl, 4-F97 243-244 (AcOEt) 61 Me Cl 3,4-Me₂ 86 225-227 (AcOEt) 62 Br Me H 82256-257 (THF) 63 OMe Cl H 61 254-257 (AcOH-H₂O)

Reference Example 64-65

The compounds of table 28 were obtained by the method similar to that inReference Example 27.

TABLE 28

Ref.Ex. Yield Melting Point (° C.) number R (%) (Recrystallizationsolvent) 64 3-Cl 82 164-165 (AcOEt) 65 4-CF₃ 37 134-135 (Et₂O-hexane)

Reference Example 66-67

The compounds of table 29 were obtained by the method similar to that inReference Example 28.

TABLE 29

Ref.Ex. Yield Melting Point (° C.) number R (%) (Recrystallizationsolvent) 66 3-Cl 89 173 (decomp.) (AcOEt) 67 4-CF₃ 84 245 (decomp.)(Et₂O-IPE)

Example 134-153

The compounds of table 30 were obtained by the method similar to that inExample 1.

TABLE 30

Example Yield Melting Point (° C.) number R¹ R² R³ R⁴ (%)(Recrystallization solvent) 134 (CH₂)₂CO 3-Cl 2,6-(i-Pr)₂ 11 232-234(THF-AcOEt) 135 (CH₂)₂CO 3-Me 2,6-(i-Pr)₂ 4 203-206 (THF-AcOEt) 136CO(CH₂)₂ 3-Cl 2,6-(OMe)₂ 46 268-271 (THF-AcOEt) 137 Me Cl 3-Cl 2,6-Me₂,4-Cl 16 292-295 (THF-IPE) 138 Me Cl 3-Cl 2-Me, 4-Cl 42 247-249(AcOEt-IPE) 139 Me Cl 3-Cl 2-Me, 4-F 74 242-245 (AcOEt-IPE) 140 Me Cl3-Cl 2-CH₂OH, 4-Cl 41 150 (decomp.) (THF-AcOEt) 141 Me Cl 3-Cl 2-CH₂OMe,4-Cl 34 180-184 (AcOEt-IPE) 142 Me Cl 3-Cl 2-CH₂OC₂H₄OMe, 48 126-128(AcOEt-IPE) 4-Cl 143 Me Cl 3-Cl 2-Me 79 239-240 (AcOEt-IPE) 144 Me Cl3-Cl 2-Et 80 201-203 (AcOEt-IPE) 145 Me Cl 3-Cl 2-iPr 64 205-207(AcOEt-IPE) 146 Me Cl 3-Cl 2-Et, 4-Cl 66 228-231 (THF-AcOEt) 147 Me Cl3-Cl 2-Et, 4-F 37 226-227 (THE-AcOEt) 148 Me Cl 3-Cl 2,3-Me₂ 56 250-251(THF-AcOEt) 149 Me Cl 3-Cl 2,4-Me₂ 69 220-222 (AcOEt-IPE) 150 Me Cl 3-Cl2,5-Me₂ 59 224-226 (AcOEt-IPE) 151 Me Cl 3-Cl 2,3-(CH₂)4 48 242-247(AcOEt-IPE) 152 Me Cl 3-Cl 2,4-Cl₂ 54 207-210 (AcOEt-IPE) 153 Me Cl 3-Cl2-Cl, 4-F 44 211-213 (AcOEt-IPE)

Example 154-179

The compounds of table 31 were obtained by the method similar to that inExample 15.

TABLE 31

Example Yield Melting Point (° C.) number R¹ R² R³ R⁴ (%)(Recrystallization solvent) 154 (CH₂)₂CO 3-Cl 2-CF₃, 4-Cl 31 180(decomp.) (AcOEt) 155 (CH₂)₂CO 3-Cl 2-CF₃, 4-F 27 150 (decomp.) (AcOEt)156 CO(CH₂)₂ 4-CF₃ 2-CF₃, 4-F 34 146-148 (THF-IPE) 157 CO(CH₂)₂ H 2-CF₃,4-Cl 32 257-260 (THF-AcOEt) 158 CO(CH₂)₂ H 2-CF₃, 4-F 51 257-259(THF-AcOEt) 159 (CH₂)₄ H 2-CF₃, 4-Cl 85 232-234 (THF-AcOEt) 160 (CH₂)₄ H2-CF₃, 4-F 47 231-232 (AcOEt) 161 (CH₂)₃ 3,4-Me₂ 2-CF₃, 4-Cl 83 236-238(AcOEt) 162 (CH₂)₃ 3,4-Me₂ 2-CF₃, 4-F 71 253-254 (AcOEt) 163 (CH₂)₃3-Cl, 4-F 2-CF₃, 4-Cl 85 221-223 (AcOEt) 164 (CH₂)₃ 3-Cl, 4-F 2-CF₃, 4-F57 219-222 (AcOEt) 165 (CH₂)₄ 3-Me 2-CF₃, 4-Cl 42 192-196 (AcOEt-IPE)166 (CH₂)₄ 3-Me 2-CF₃, 4-F 60 215-216 (AcOEt-IPE) 167 Me 3-Cl 2-CF₃, 4-F50 210-211 (AcOEt-hexane) 168 (CH₂)₃ 3-Cl 2-CF₃, 4-Cl 78 215-219(AcOEt-hexane) 169 (CH₂)₃ 3-Cl 2-CF₃, 4-F 82 219-222 (AcOEt-hexane) 170(CH₂)₄ 3-Cl 2-CF₃, 4-Cl 40 214-217 (AcOEt-hexane) 171 (CH₂)₄ 3-Cl 2-CF₃,4-F 45 220-224 (AcOEt-hexane) 172 Me Cl 4-CF₃ 2-CF₃, 4-Cl 71 261-264(AcOEt-IPE) 173 Me Cl 4-CF₃ 2-CF₃, 4-F 67 250-252 (AcOEt-IPE) 174 Me Cl3,4-Me₂ 2-CF₃, 4-Cl 67 253-254 (THF-IPE) 175 Me Cl 3,4-Me₂ 2-CF₃, 4-F 67240-241 (THF-IPE) 176 Br Me H 2-CF₃, 4-Cl 58 223-225 (AcOEt) 177 Br Me H2-CF₃, 4-F 56 237-238 (AcOEt) 178 OMe Cl H 2-CF₃, 4-Cl 81 246-247(THF-EtOH) 179 OMe Cl H 2-CF₃, 4-F 52 218-220 (THF-EtOH)

Example 180-202

The compounds of table 32 and table 33 were obtained by the methodsimilar to that in Example 74.

TABLE 32

Example Yield Melting Point (° C.) number R¹ R² R³ (%)(Recrystallization solvent) 180 NHMe CF₃ Cl 65 205-207 (AcOEt) 181NH(CH₂)₃O(CH₂)₃CH₃ CF₃ Cl 104-106 (ACOEt-hexane) 182 NEt₂ CF₃ Cl 87163-164 (AcOEt-IPE) 183

CF₃ Cl 58 159 (AcOEt-IPE) 184

CF₃ Cl 73 205-208 (AcOEt-IPE) 185

CF₃ Cl 49 158-160 (AcOEt-IPE) 186

CF₃ Cl 50 173-175 (AcOEt-IPE) 187

CF₃ Cl 96 205-207 (AcOEt-IPE) 188

CF₃ Cl 77 193 (decomp.) (AcOEt-IPE) 189

CF₃ Cl 74 191-194 (AcOEt-IPE) 190

CF₃ Cl 86 203-207 (AcOEt)

TABLE 33

191

CF₃ Cl 89 194-197 (AcOEt-IPE) 192

CF₃ Cl 73 196-197 (AcOEt-IPE) 193

CF₃ Cl 20 201-204 (AcOEt-IPE) 194

CF₃ Cl 32 186-188 (AcOEt) 195

CF₃ Cl 20 219-220 (THF-IPE) 196 NEt₂ CF₃ F 25 206-207 (AcOEt-hexane) 197

CF₃ F 87 200-206 (AcOEt-hexane) 198

CF₃ F 83 203-204 (AcOEt-hexane) 199

CF₃ F 82 216-218 (AcOEt-IPE) 200

CF₃ F 84 198-200 (AcOEt-EtOH) 201

CF₃ F 32 207-208 (THF-TPE) 202

Me Cl 22 239-241 (THF-IPE)

Example 203

Synthesis of2-[7-chloro-2-oxo-4-phenyl-6-[(pyridine-2-ylthio)methyl]-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide

A solution of2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]acetic acid(0.21 g) in THF (5 ml) was combined with DMF (1 drop) and oxalylchloride (86 ml), and stirred at room temperature for 1 hour. Thereaction solution was concentrated under reduced pressure, and theresultant residue was dissolved in THF (3 ml) and added dropwise to asuspension of 4-chloro-2-trifluoromethylaniline (72 ml) and sodiumhydride (60%, in oil) (23 mg) in THF (2 ml) at 0° C. After stirring atroom temperature for 12 hours, the reaction solution was combined withwater, and the product was extracted with ethyl acetate. The extract waswashed with a 1 N solution of hydrochloric acid followed by a saturatedaqueous solution of sodium chloride, a saturated aqueous solution ofsodium hydrogen carbonate and a saturated aqueous solution of sodiumchloride, and after drying over magnesium sulfate, the solvent wasdistilled off under reduced pressure. The resultant residue wasdissolved in THF (10 ml), combined with 2-mercaptopyridine (0.088 g) andDBU (0.118 ml), and stirred at room temperature for 24 hours. Thereaction solution was combined with water, and extracted with ethylacetate. The extract was washed with a saturated brine, and then driedover magnesium sulfate, and concentrated under reduced pressure. Theresultant residue was recrystallized from ethyl acetate-diisopropylether to obtain the title compound as a colorless crystal (205 mg, 65%).Melting point: 213-215° C.

Example 204

Synthesis of2-[7-chloro-2-oxo-4-phenyl-6-[(pyridin-2-ylthio)methyl]-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide

The title compound (yield: 71%) was obtained by the method similar tothat in Example 203. Melting Point: 195-196° C. (AcOEt-IPE).

Example 205

Synthesis of2-[6-[[acetyl(methyl)amino]methyl]-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide

A solution of2-[6-[(methylamino)methyl]-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide(Example 180)(0.20 g) in THF (5 ml) was combined with triethylamine(0.11 ml) and acetyl chloride (0.033 ml), and stirred for 3 hours. Thereaction solution was combined with water and extracted with ethylacetate. The extract was washed with a saturated aqueous solution ofsodium bicarbonate followed by a saturated brine, and then dried overmagnesium sulfate, and concentrated under reduced pressure. Theresultant residue was purified by column chromatography (packing: silicagel, eluent: ethyl acetate-hexane=1:4), and further recrystallized fromethyl acetate-diisopropyl ether to obtain the title compound as acolorless crystal (105 mg, 48%). Melting point: 199-201° C.

Example 206

Synthesis of2-[6-[[benzoyl(methyl)amino]methyl]-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide

The title compound (yield: 66%) was obtained by the method similar tothat in Example 205. Melting Point: 215-216° C. (AcOEt-Hexane).

Example 207

Synthesis of2-[7-chloro-2-oxo-4-phenyl-6-(piperazin-1-yl)methyl-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide

A solution of2-6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]acetic acid(0.28 g) in THF (7 ml) was combined with DMF (1 drop) and oxalylchloride (120 ml), and stirred at room temperature for 1 hour. Thereaction solution was concentrated under reduced pressure to obtain theresidue, which was dissolved in THF (5 ml) and added dropwise to asuspension of 4-chloro-2-trifluoromethylaniline (101 ml) and sodiumhydride (60%, in oil) (32 mg) in THF (3 ml) at 0° C. After stirring atroom temperature for 12 hours, the reaction solution was combined withwater, and the product was extracted with ethyl acetate. The extract waswashed with a 1 N solution of hydrochloric acid followed by a saturatedaqueous solution of sodium chloride, a saturated aqueous solution ofsodium hydrogen carbonate and a saturated aqueous solution of sodiumchloride, and after drying over magnesium sulfate, the solvent wasdistilled off under reduced pressure. The resultant residue wasdissolved in THF (10 ml), combined with tert-butyl1-piperidinecarboxylate (0.191 g) and triethylamine (0.14 ml), andheated under reflux for 5 hours. The reaction solution was combined withwater and extracted with ethyl acetate. The extract was washed with asaturated brine, dried over magnesium sulfate, and then concentratedunder reduced pressure. The resultant residue was dissolved in aceticacid (10 ml), combined with concentrated hydrochloric acid (10 ml), andthen heated under reflux for 30 minutes. The reaction solution wascombined with water and extracted with ethyl acetate. The extract waswashed with a saturated sodium bicarbonate followed by a saturatedbrine, dried over magnesium sulfate, and then the extract wasconcentrated under reduced pressure. The resultant residue wasrecrystallized from ethyl acetate-diisopropyl ether to obtain the titlecompound as a colorless crystal (122 mg, 30%). Melting point: 237-242°C.

Example 208

Synthesis of2-(7-chloro-6-hydroxy-2-oxo-4-phenyl-2H-chromen-3-yl)-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide

A solution of2-(7-chloro-6-methoxy-2-oxo-4-phenyl-2H-chromen-3-yl)-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide(Example 178) (3.20 g) in methylene chloride (10 ml) was combined with a1 M solution of boron tribromide/methylene chloride (31.6 ml, 13.6mmol), and stirred at room temperature for 3 days. The reaction solutionwas poured into an ice water, to which concentrated hydrochloric acidwas then added. The precipitate was filtered and washed with isopropanolfollowed by ether to obtain the title compound as a colorless crystal(2.05 g, 64%). An aliquot was recrystallized from THF-isopropyl ether tomeasure a melting point. Melting point: 246-247° C.

Example 209

Synthesis of2-(7-chloro-6-hydroxy-2-oxo-4-phenyl-2H-chromen-3-yl)-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide

The title compound (yield: 58%) was obtained by the method similar tothat in Example 208. Melting Point: 240-243° C. (AcOEt-Hexane).

Example 210

Synthesis of2-(7-chloro-2-oxo-4-phenyl-6-(2-propoxyethoxy)-2H-chromene-3-yl)-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide

A solution of2-(7-chloro-6-hydroxy-2-oxo-4-phenyl-2H-chromen-3-yl)-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide(Example 208) (0.30 g) in DMF (5 ml) was combined with 2-chloroethylethyl ether (0.31 ml), potassium carbonate (0.23 g) and sodium iodide(0.15 g), and stirred at 120° C. for 30 minutes. The reaction solutionwas combined with water and extracted with ethyl acetate. The extractwas washed with a saturated brine, and then dried over magnesiumsulfate, and concentrated under reduced pressure. The resultant residuewas recrystallized from ethyl acetate-diisopropyl ether to obtain thetitle compound as a colorless crystal (151 mg, 43%). Melting point:170-171° C.

Example 211-213

The compounds of table 34 were obtained by the method similar to that inExample 210.

TABLE 34

Melting Point (° C.) Example Yield (Recrystallization number R¹ R² (%)solvent) 211 O(CH₂)₂O(CH₂)₂CH₃ F 32% 161-162 (AcOEt-IPE) 212 O(CH₂)₂OPhCl 54% 176-177 (AcOEt-IPE) 213 O(CH₂)₂OPh F 52% 189-190 (AcOEt-IPE)

Example 214

Synthesis ofN-[4-fluoro-2-(trifluoromethyl)phenyl]-2-(8-hydroxy-2-oxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetamide

A suspension of NaBH₄ (30 mg) in DME (2 ml) was combined with2-(2,8-dioxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)-N-[4-fluoro-2-(trifluoromethyl)phenyl]-acetamide(Example 88) (170 mg) with cooling in ice, and further combined withmethanol, and stirred at room temperature for 10 minutes. The reactionsolution was poured into diluted hydrochloric acid, which was thenextracted with ethyl acetate. The extract was washed with water, andthen dried over magnesium sulfate, and concentrated under reducedpressure to obtain the title compound as a colorless crystal (110 mg,yield: 65%). An aliquot was recrystallized from ethyl acetate to measurea melting point. Melting point: 217-218° C.

Example 215

Synthesis ofN-[4-fluoro-2-(trifluoromethyl)phenyl]-2-[8-hydroxy-4-(3-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl]acetamide

The title compound (yield: 82%) was obtained by the method similar tothat in Example 214. Melting Point: 225-227° C. (AcOEt).

Example 216

Synthesis ofN-[4-fluoro-2-(trifluoromethyl)phenyl]-2-(4-phenyl-2-oxo-2,6-dihydrocyclopenta[g]chromen-3-yl)acetamide

A solution ofN-[4-fluoro-2-(trifluoromethyl)phenyl]-2-(8-hydroxy-2-oxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetamide(Example 214) (250 mg) in toluene (50 ml) was combined with p-TsOHmonohydrate (300 mg), and heated under reflux for 30 minutes. After thereaction solution was concentrated, the resultant residue was purifiedby a silica gel column chromatography (eluent: hexane-ethyl acetate=3:1)to obtain the title compound as a colorless crystal (200 mg, yield:74%). An aliquot was recrystallized from THF to measure a melting point.Melting point: 217-218° C.

Example 217

Synthesis ofN-[4-fluoro-2-(trifluoromethyl)phenyl]-2-[4-(3-methylphenyl)-2-oxo-2,6-dihydrocyclopenta[g]chromen-3-yl]acetamide

The title compound (yield: 55%) was obtained by the method similar tothat in Example 216. Melting Point: 196-197° C. (AcOEt-Hexane).

Example 218

Synthesis of Methyl(2E)-3-[3-[2-[[4-fluoro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl]-7-methyl-2-oxo-4-phenyl-2H-chromen-6-yl]propenoate

A solution of2-(6-bromo-7-methyl-2-oxo-4-phenyl-2H-chromen-3-yl)-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide(Example 177) (500 mg) in DMF (5 mL) was combined with methyl acrylate(0.14 mL), Et₃N (0.21 mL), Pd(OAc)₂ (5 mg) and triphenylphosphine (10mg) under argon atmosphere, and stirred with heating at 120° C. for 10hours. The reaction solution was combined with water and extracted withethyl acetate. The extract was washed with diluted hydrochloric acidfollowed by an aqueous solution of NaHCO₃ and water, and then dried overmagnesium sulfate, and concentrated under reduced pressure to obtain thetitle compound as a colorless crystal (360 mg, yield: 72%). An aliquotwas recrystallized from ethyl acetate to measure a melting point.Melting point: 233-236° C.

Reference Example 68

Synthesis of ethyl2-(6,7-dimethyl-2-oxo-4-phenyl-2H-chromen-3-yl)acetate

The title compound (yield: 75%) was obtained by the method similar tothat in Reference Example 21. Melting point: 127-128° C. (AcOEt-Hxane)

Reference Example 69

Synthesis of ethyl2-[6,7-bis(acetoxymethyl)-2-oxo-4-phenyl-2H-chromen-3-yl]acetate

A solution of ethyl2-(6,7-dimethyl-2-oxo-4-phenyl-2H-chromene-3-yl)acetate (0.50 g) inethyl acetate (20 ml) was combined with N-bromosuccinimide (0.66 g) and2,2′-azoisobutyronitrile (24.4 mg), and heated under reflux for 1 hour.After cooling, the reaction solution was washed with water followed by asaturated aqueous solution of sodium hydrogen carbonate and a saturatedaqueous solution of sodium chloride. After drying over magnesiumsulfate, the solvent was distilled off under reduced pressure. Theresultant residue was dissolved in DMF (10 ml), combined with anhydroussodium acetate (488 mg), and stirred at 60° C. for 5 hours. The reactionsolution was combined with water, and the product was extracted withethyl acetate, and the extract was washed with a saturated aqueoussolution of sodium chloride. After drying over magnesium sulfate, thesolvent was distilled off under reduced pressure. The resultant residuewas purified by a silica gel column chromatography (eluent: ethylacetate-hexane), and further recrystallized from ether-diisopropyl etherto obtain the title compound (281 mg, yield: 42%). Melting point: 95-96°C.

Reference Example 70

Synthesis of Ethyl2-[6,7-bis(hydroxymethyl)-2-oxo-4-phenyl-2H-chromen-3-yl]acetate

A solution of ethyl2-[6,7-bis(acetoxymethyl)-2-oxo-4-phenyl-2H-chromen-3-yl]acetate (240mg) in ethanol (4 ml) was combined with DBU (0.4 ml), and stirred atroom temperature for 30 minutes. The reaction solution was diluted withethyl acetate (30 ml), and then washed with a 1 N solution ofhydrochloric acid followed by a saturated aqueous solution of sodiumchloride, a saturated aqueous solution of sodium hydrogen carbonate anda saturated aqueous solution of sodium chloride, and after drying overmagnesium sulfate, the solvent was distilled off under reduced pressure.The resultant residue was recrystallized from ether to obtain the titlecompound (167 mg, yield: 86%). Melting point: 130-131° C.

Reference Example 71

Synthesis of ethyl2-(2,8-dioxo-4-phenyl-6,8-dihydro-2H-furo[3,4-g]chromen-3-yl)acetate

A solution of ethyl2-[6,7-bis(hydroxymethyl)-2-oxo-4-phenyl-2H-chromen-3-yl]acetate (150mg) in dichloromethane (3 ml) was combined with manganese dioxide (1.5g), and stirred at room temperature overnight. After the catalyst wasfiltered off, the filtrate was concentrated under reduced pressure toobtain the residue, which was recrystallized from THF to obtain thetitle compound (98 mg, yield: 66%).

Melting point: 222-223° C.

Reference Example 72

Synthesis of2-(2,8-dioxo-4-phenyl-6,8-dihydro-2H-furo[3,4-g]chromen-3-yl)acetic acid

Ethyl2-(2,8-dioxo-4-phenyl-6,8-dihydro-2H-furo[3,4-g]chromen-3-yl)acetate (58mg) was dissolved in acetic acid (2 ml) and concentrated hydrochloricacid (1 ml), and heated under reflux for 30 minutes. The reactionsolution was concentrated under reduced pressure to obtain the residue,which was dissolved in a solvent mixture of THF (10 ml) and ethylacetate (50 ml), and then washed with water followed by a saturatedaqueous solution of sodium chloride. After drying over magnesiumsulfate, the solvent was distilled off under reduced pressure, and theresidue was recrystallized from THF-isopropyl ether to obtain the titlecompound (72 mg, yield: 92%). Melting point: 226-227° C.

Example 219

Synthesis of2-[7-chloro-6-(cyanomethyl)-2-oxo-4-phenyl-2H-chromen-3-yl]-N-(4-chloro-2-trifluoromethylphenyl)acetamide

A solution of2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]acetic acid(1.6 g) in THF (40 ml) was combined with DMF (5 drops) and oxalylchloride (0.7 ml), and stirred at room temperature for 1 hour. Thereaction solution was concentrated under reduced pressure to obtain theresidue, which was dissolved in THF (20 ml) and added dropwise to asuspension of 4-chloro-2-trifluoromethylaniline (0.55 ml) and sodiumhydride (60%, in oil) (176 mg) in THF (20 ml) at 0° C. After stirring atroom temperature for 12 hours, the reaction solution was combined withwater, and the product was extracted with ethyl acetate. The extract waswashed with a 1 N solution of hydrochloric acid followed by a saturatedaqueous solution of sodium chloride, a saturated aqueous solution ofsodium hydrogen carbonate and a saturated aqueous solution of sodiumchloride, and after drying over magnesium sulfate, the solvent wasdistilled off under reduced pressure. The resultant crude crystal of2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromene-3-yl]-N-(4-chloro-2-trifluoromethylphenyl)acetamidewas dissolved in DMF (6 ml), combined with sodium cyanide (0.13 g), andstirred for 3 hours. The reaction solution was combined with water toform a precipitate, which was filtered and washed with water followed bymethanol and ether. The precipitate thus obtained was purified by asilica gel column chromatography (eluent: chloroform-ethylacetate-hexane=5:1:4), and further recrystallized from THF-diisopropylether to obtain the title compound (480 mg, yield: 55%). Melting point:247-248° C.

Example 220

Synthesis of2-[6-(aminoethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]-N-(4-chloro-2-trifluoromethylphenyl)acetamide

A solution of2-[7-chloro-6-(cyanomethyl)-2-oxo-4-phenyl-2H-chromen-3-yl]-N-(4-chloro-2-trifluoromethylphenyl)acetamide(100 mg) in THF (5 ml) was combined with Raney-cobalt (100 mg), andstirred under hydrogen atmosphere (4.5 atm) at room temperature for 7hours. After the catalyst was filtered off, the filtrate wasconcentrated under reduced pressure to obtain the residue, which wasrecrystallized from ethyl acetate to obtain the title compound (27 mg,yield: 27%). Melting point: 165-167° C.

Example 221

Synthesis of2-(2,8-dioxo-4-phenyl-6,8-dihydro-2H-furo[3,4-g]chromen-3-yl)-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide

The title compound (yield: 71%) was obtained by the method similar tothat in Example 15. Melting Point: 253-254° C. (AcOEt-IPE).

Example 222

Synthesis of2-[7-chloro-6-[(1-oxide-4-phenyl-1-piperazinyl)methyl]-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide

A solution of2-[7-chloro-2-oxo-4-phenyl-6-[(4-phenyl-1-piperazinyl)methyl]-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide(1.0 g) in chloroform (5 ml) was combined with mCPBA (0.41 g), andstirred at room temperature for 30 minutes. The reaction solution wassubjected as it was to a silica gel column chromatography (eluent: ethylacetate-methanol-aqueous ammonia=85:15:1) for purification, and followedby recrystallization from ethyl acetate-diisopropyl ether to obtain thetitle compound (218 mg, yield: 21%). Melting point: 157-159° C.

Example 223

Synthesis of2-[7-chloro-6-[(4-oxide-4-phenyl-1-piperazinyl)methyl]-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide

A solution of2-[7-chloro-2-oxo-4-phenyl-6-[(4-phenyl-1-piperazinyl)methyl]-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide(1.0 g) in chloroform (5 ml) was combined with mCPBA (0.41 g), andstirred at room temperature for 30 minutes. The reaction solution wassubjected as it was to a silica gel column chromatography (eluent: ethylacetate-methanol-aqueous ammonia=85:15:1) to fractionate2-[7-chloro-6-[(1-oxide-4-phenyl-1-piperazinyl]methyl]-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide(Example 222), after which the remaining trace components were furtherpurified by HPLC (CHIRALCEL OD, hexane-ethanol=8:2) to obtain the titlecompound (71 mg, yield: 7%). Melting point: 183-184° C.

Example 224

Synthesis of2-[7-chloro-2-oxo-4-phenyl-6-[(4-phenyl-1-piperazinyl)methyl]-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamidehydrochloride

A solution of2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]acetic acid(0.41 g) in THF (10 ml) was combined with DMF (1 drop) and oxalylchloride (0.2 ml), and stirred at room temperature for 1 hour. Thereaction solution was concentrated under reduced pressure to obtain theresidue, which was dissolved in THF (5 ml) and added dropwise to asuspension of 4-chloro-2-trifluoromethylaniline (0.14 ml) and sodiumhydride (60%, in oil) (44 mg) in THF (5 ml) at 0° C. After stirring atroom temperature for 12 hours, the reaction solution was combined withwater, and the product was extracted with ethyl acetate. The extract waswashed with a 1 N solution of hydrochloric acid followed by a saturatedaqueous solution of sodium chloride, a saturated aqueous solution ofsodium hydrogen carbonate and a saturated aqueous solution of sodiumchloride, and after drying over magnesium sulfate, the solvent wasdistilled off under reduced pressure. A solution of the resultant crudecrystal of2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl-N-(4-chloro-2-trifluoromethylphenyl)acetamidein DMF (10 ml) was combined with 1-phenyl-piperazine (0.166 g) andpotassium carbonate (0.285 g), and stirred at 80° C. for 30 minutes.After cooling, the reaction solution was diluted with ethyl acetate (5ml), and poured into water (120 ml). The precipitate formed was filteredand washed with water (20 ml) followed by ethanol (10 ml). The crystalfiltered was dissolved in THF (6 ml), and then combined withconcentrated hydrochloric acid (0.26 ml), and stirred for 20 minutes.The precipitate was filtered, and washed with ethyl acetate to obtainthe title compound (491 mg, yield: 70%). Melting point: 238-239° C.

Example 225

Synthesis of2-[7-chloro-2-oxo-4-phenyl-6-[(4-phenyl-1-piperazinyl)methyl]-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamidemethansulfonate

The title compound (yield: 67%) was obtained by the method similar tothat in Example 224. Melting Point: 198-204° C. (THF-EtOH).

Example 226

Synthesis of2-[7-chloro-2-oxo-4-phenyl-6-[(4-phenyl-1-piperazinyl)methyl]-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide(Alternative Synthesis Method of the Compound of Example 75)

A solution of2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]acetic acid(0.41 g) in THF (10 ml) was combined with DMF (1 drop) and oxalylchloride (0.2 ml), and stirred at room temperature for 1 hour. Thereaction solution was concentrated under reduced pressure to obtain theresidue, which was dissolved in THF (5 ml) and added dropwise to asuspension of 4-chloro-2-trifluoromethylaniline (0.14 ml) and sodiumhydride (66%, in oil) (44 mg) in THF (5 ml) at 0° C. After stirring atroom temperature for 12 hours, the reaction solution was combined withwater, and the product was extracted with ethyl acetate. The extract waswashed with a 1 N solution of hydrochloric acid followed by a saturatedaqueous solution of sodium chloride, a saturated aqueous solution ofsodium hydrogen carbonate and a saturated aqueous solution of sodiumchloride, and after drying over magnesium sulfate, the solvent wasdistilled off under reduced pressure. A solution of the resultant crudecrystal of2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]-N-(4-chloro-2-trifluoromethylphenyl)acetamidein DMF (10 ml) was combined with 1-phenyl piperazine (0.166 g) andpotassium carbonate (0.285 g), and stirred at 80° C. for 30 minutes.After cooling, the reaction solution was diluted with ethyl acetate (5ml), and poured into water (120 ml). The precipitate formed wasfiltered, and washed with water (20 ml) followed by ethanol (10 ml). Thecrystal filtered was dissolved in THF (6 ml), and then combined withconcentrated hydrochloric acid (0.26 ml), and stirred for 20 minutes.The precipitate was filtered and washed with ethyl acetate. A suspensionof the precipitate filtered in ethanol (10 ml) was combined with asaturated aqueous solution of sodium hydrogen carbonate (30 ml), andstirred for 20 minutes. The precipitate was filtered and washed withwater (20 m) followed by ethanol (10 ml). The crystal filtered wasdissolved in THF (20 ml), and then dried over magnesium sulfate, andthen concentrated under reduced pressure. The resultant residue wasrecrystallized from THF-ethanol to obtain the title compound as acolorless crystal (0.431 g, yield: 63%). Melting point: 201-203° C.

Reference Example 73

Synthesis of ethyl[7-chloro-2-oxo-4-phenyl-6-[(4-phenylpiperazin-1-yl)methyl]-2H-chromen-3-yl]acetate.hydrochloride

Ethyl (7-chloro-6-methyl-2-oxo-4-phenyl-2H-chromen-3-yl)acetate (100 g),N-bromosuccinimide (59.9 g) and 2-2′-azobis-2,4-dimethylvaleronitrile(3.48 g) were suspended in AcO^(t)Bu (700 ml) under nitrogen atmosphere,and stirred at 80° C. for 2 hours. The reaction solution was cooled, andtreated dropwise with triethylamine (34.03 g) at 25° C. or lower over 10minutes, followed by treatment dropwise with phenylpiperazine (45.47 g)at 40° C. or lower internal temperature over 15 minutes. Aftercompleting dropwise addition, the mixture was stirred for 2 hours. Tothe reaction solution was added dropwise ethanol (500 ml) over 15minutes, and further added dropwise water (200 ml) over 15 minutes.After completing dropwise addition, the mixture was stirred at roomtemperature for 30 minutes, and further stirred with cooling in ice for1 hour. The crystal formed was filtered and washed with 50% ethanol toobtain the crude crystal (100 g, yield: 69%) of ethyl[7-chloro-2-oxo-4-phenyl-6-[(4-phenylpiperazine-1-yl)methyl]-2H-chromene-3-yl]acetate.

The resultant crude crystal (70 g) was suspended in a mixture solutionof ethanol (280 ml) and AcO^(t)Bu (280 ml), and combined withconcentrated hydrochloric acid (12.2 ml) at 40° C. After stirring at 40°C. for 30 minutes, the mixture was cooled to room temperature, andfurther cooled with cooling in ice, and stirred for 1 hour. The crystalformed was filtered and washed with 50% ethanol to obtain the titlecompound (72 g, yield: 96%) as a white crystal.

NMR (CDCl₃) δ: 1.23 (3H, t, J=7 Hz), 3.20-3.50 (4H, m), 3.41 (2H, s),3.50-3.65 (2H, m), 3.70-3.90 (2H, m), 4.14 (2H, q, J=7 Hz), 4.20-4.35(2H, m), 6.95-7.10 (3H, m), 7.20-7.40 (5H, m), 7.52 (1H, s), 7.50-7.65(3H, m), 7.80-7.90 (1H, brs).

Reference Example 74

Synthesis of[7-chloro-2-oxo-4-phenyl-6-[(4-phenylpiperazin-1-yl)methyl]-2H-chromen-3-yl]aceticacid

Ethyl[7-chloro-2-oxo-4-phenyl-6-[(4-phenylpiperazin-1-yl)methyl]-2H-chromen-3-yl]acetate.hydrochloride(40 g) was suspended in ethanol (120 ml), and combined with a 2 Naqueous solution of sodium hydroxide (144.5 ml). A yellow clear solutionobtained by stirring at 70° C. for 1 hour was added dropwise to amixture solution of ethanol (40 ml) and 6 N hydrochloric acid (49.4 ml)over 45 minutes. The reaction solution was adjusted to pH 5.5 to 6.0with sodium hydrogen carbonate at 40° C. After pH became stable, themixture was stirred at 35 to 40° C. internal temperature for 15 minutes,and cooled to room temperature, and stirred at room temperature for 30minutes. The crystal formed was filtered and washed with 30% ethanol toobtain the title compound (34 g, yield: 96%) as a white crystal.

NMR (CDCl₃) δ: 2.45-2.70 (2H, m), 2.90-3.25 (3H, m), 3.39 (2H, s),3.40-3.85 (4H, m), 4.20-4.40 (2H, m), 6.80-7.00 (2H, m), 7.10-7.70 (10H,m).

Reference Example 75

Synthesis of[6-(bromomethyl)-7-chloro-4-(3-chlorophenyl)-2-oxo-2H-chromene-3-yl]aceticacid

The title compound was obtained by the method similar to that inReference Example 24.

NMR (CDCl₃) δ: 3.36 (1H, d, J=17 Hz), 3.47 (1H, d, J=17 Hz), 4.60 (2H,s), 7.07 (1H, s), 7.18 (1H, m), 7.28 (1H, m), 7.48 (1H, s), 7.55 (2H,m).

Example 227

Synthesis of2-[7-chloro-2-oxo-4-phenyl-6-[(4-phenyl-1-piperazinyl)methyl]-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide(Alternative Synthesis Method of the Compound of Example 75)

[7-Chloro-2-oxo-4-phenyl-6-[(4-phenylpiperazine-1-yl)methyl]-2H-chromen-3-yl]aceticacid (500 g) was suspended in a mixture solution of THF (5 L) and DMF (5ml), and cooled to 5° C. or lower with cooling in ice. Thionyl chloride(150 ml) was added dropwise at the same temperature. After completingdropwise addition, the mixture was allowed to warm to room temperature,and stirred at 25 to 30° C. for 5 hours. The reaction solution wascombined with toluene (2 L) and concentrated under reduced pressure. Theresultant residue was suspended in THF (5 L), combined with4-chloro-2-(trifluoromethyl)aniline (250 g), and refluxed at 80° C. for5 hours. The reaction solution was cooled to 40° C., and combined withacetone (5 L) and water (2.5 L). The mixture was adjusted to pH 7.6 with25% aqueous ammonia, and stirred at 15 to 20° C. for 30 minutes. Thecrystal precipitated was separated by centrifugal separator, and washedwith acetone and water to obtain the title compound (487 g, yield: 71%).

Melting point: 201-203° C.

Example 228-248

The compounds of table 35 were obtained by the method similar to that inExample 74.

TABLE 35

Example Yield Melting Point (° C.) number R¹ R² (%) (Recrystallizationsolvent) 228 4-Cl 2-CF₃, 4-Cl 47 215-217 (AcOEt-hexane) 229 4-Cl 2-CF₃,4-F 22 185-187 (THF-AcOEt) 230 3-Cl 2-CF₃, 4-Cl 42 203-205(AcOEt-hexane) 231 3-Cl 2-CF₃, 4-F 59 180-182 (THF-AcOEt) 232 4-F 2-CF₃,4-Cl 48 205-208 (AcOEt-hexane) 233 4-F 2-CF₃, 4-F 43 201-202 (THF-AcOEt)234 3-F 2-CF₃, 4-Cl 86 196-199 (THF-AcOEt) 235 3-F 2-CF₃, 4-F 61 180-182(THF-AcOEt) 236 3,4-F₂ 2-CF₃, 4-Cl 55 192-195 (THF-AcOEt) 237 3,4-F₂2-CF₃, 4-F 46 196-199 (THF-AcOEt) 238 3,4-F₂ 2-Me, 4-Cl 55 203-206(THF-AcOEt) 239 3-Me 2-CF₃, 4-Cl 58 190-192 (THF-AcOEt) 240 3-Me 2-CF₃,4-F 49 168-170 (THF-AcOEt) 241 3-Me 2-Me, 4-Cl 67 235-238 (THF-AcOEt)242 3,4-(Me)₂ 2-CF₃, 4-Cl 70 208-211 (THF-AcOEt) 243 3,4-(Me)₂ 2-CF₃,4-F 77 186-187 (THF-AcOEt) 244 3-CF₃ 2-CF₃, 4-Cl 41 183-186(AcOEt-hexane) 245 3-CF₃ 2-CF₃, 4-F 62 198-201 (THF) 246 3-CF₃ 2-Me,4-Cl 89 232-234 (THF) 247 2,3,5-(Me)₃, 4-OH 2-CF₃, 4-Cl 22 216-218(THF-AcOEt) 248 2,3,5-(Me)₃, 4-OH 2-CF₃, 4-F 22 220-221 (THE-AcOEt)

Example 249-268

The compounds of table 36 were obtained by the method similar to that inExample 74.

TABLE 36

Example Yield Melting Point (° C.) number R¹ R² (%) (Recrystallizationsolvent) 249 H 2-Me, 4-Cl 66 213-216 (AcOEt-IPE) 250 H 2,3,4-F₃ 47169-174 (AcOEt-IPE) 251 4-Cl 2-CF₃, 4-Cl 49 194-197 (THF-AcOEt-hexane)252 4-Cl 2-CF₃, 4-F 49 178-184 (THF-AcOEt-hexane) 253 4-Cl 2-Me, 4-Cl 55218-220 (THF-AcOEt-hexane) 254 3-Cl 2-CF₃, 4-Cl 51 193-195(AcOEt-hexane) 255 3-Cl 2-CF₃, 4-F 37 170-174 (AcOEt-hexane) 256 3-Cl2-Me, 4-Cl 41 199-200 (AcOEt-hexane) 257 3-F 2-CF₃, 4-Cl 49 110-114(AcOEt-hexane) 258 3-F 2-CF₃, 4-F 40 184-187 (AcOEt-hexane) 259 3-F2-Me, 4-Cl 52 211-217 (AcOEt-hexane) 260 4-Me 2-CF₃, 4-Cl 56 217-222(THF-AcOEt-hexane) 261 4-Me 2-CF₃, 4-F 45 210-219 (THF-AcOEt-hexane) 2624-Me 2-Me, 4-Cl 27 189-191 (THF-AcOEt-hexane) 263 3-Me 2-CF₃, 4-Cl 47183-188 (AcOEt-hexane) 264 3-Me 2-CF₃, 4-F 37 134-135 (AcOEt-hexane) 2653-Me 2-Me, 4-Cl 28 196-200 (AcOEt-hexane) 266 3-CF₃ 2-CF₃, 4-Cl 10194-196 (AcOEt) 267 3-CF₃ 2-CF₃, 4-F 53 164-167 (AcOEt-hexane) 268 3-CF₃2-Me, 4-Cl 14 120 (decomp.) (AcOEt)

Example 269-271

The compounds of table 37 were obtained by the method similar to that inExample 74.

TABLE 37

Example Yield Melting Point (° C.) number R (%) (Recrystallizationsolvent) 269 2-CF₃, 4-Cl 33 208-211 (AcOEt-hexane) 270 2-CF₃, 4-F 37182-184 (AcOEt-hexane) 271 2-Me, 4-Cl 34 177-180 (AcOEt-hexane)

Example 272-273

The compounds of table 38 were obtained by the method similar to that inExample 74.

TABLE 38

Example Yield Melting Point (° C.) number R (%) (Recrystallizationsolvent) 272 Cl 52 214-217 (AcOEt-IPE) 273 F 55 203-205 (AcOEt-IPE)

Example 274-276

The compounds of table 39 were obtained by the method similar to that inExample 74.

TABLE 39

Example Yield Melting Point (° C.) number R (%) (Recrystallizationsolvent) 274 2-CF₃, 4-Cl 67 216-218 (THF-AcOEt) 275 2-CF₃, 4-F 64227-229 (THF-AcOEt) 276 2-Me, 4-Cl 73 240-242 (THF-AcOEt)

Example 277-283

The compounds of table 40 were obtained by the method similar to that inExample 203.

TABLE 40

Example Yield Melting Point (° C.) number R¹ R² (%) (Recrystallizationsolvent) 277

Cl 64 227-230 (THF-AcOEt) 278

Cl 57 262-264 (THF-AcOEt) 279

F 24 212-215 (THF-AcOEt) 280

F 43 245-247 (THF-AcOEt) 281

Cl 72 254-256 (THF-AcOEt) 282

F 59 251-253 (THF-AcOEt) 283 CH₃(CH₂)₁₁S Cl 6 120-122 (THF-AcOEt)

Reference Example 76-87

The compounds of table 41 were obtained by the method similar to that inReference Example 13.

TABLE 41

Ref.Ex. Yield Melting Point (° C.) number R¹ R² (%) (Recrystallizationsolvent) 76 Me 3-Me 80 250-253 (AcOEt) 77 Me 3,5-Me₂ 61 228-230(AcOEt-IPE) 78 Me 4-F 80 253-257 (AcOEt) 79 Me 4-Cl 87 238-241 (AcOEt)3-Cl, 80 Me 4-F 88 258 (decomp.) (AcOEt) 81 Me 3,4-F₂ 77 262-264 (AcOEt)82 Me 3-Br 93 270 (decomp.) (AcOEt) 83 Me 4-OCF₃ 93 183-186 (AcOEt) 84Me 3-OCF₃ 71 187-191 (AcOEt) 85 F H 92 209-210 (AcOEt-hexane) 86 F 3-Cl77 213-215 (IPE-hexane) 87 Me 3-NO₂ 74 260 (decomp.) (AcOEt)

Example 284-307

The compounds of table 44 were obtained by the method similar to that inExample 15.

TABLE 42

Example Yield Melting Point (° C.) number R¹ R² R³ (%)(Recrystallization solvent) 284 Me Cl 3-Me 85 235-237 (THF-AcOEt) 285 MeF 3-Me 67 218-220 (THF-AcOEt) 286 Me Cl 3,5-(Me)₂ 65 266-267 (THF) 287Me F 3,5-(Me)₂ 68 274-275 (THF) 288 Me Cl 4-Cl 80 284-286 (THF-AcOEt)289 Me F 4-Cl 77 272-273 (THF-AcOEt) 290 Me Cl 4-F 73 272-273(THF-AcOEt) 291 Me F 4-F 70 271-272 (THF-AcOEt) 292 Me Cl 3-Cl, 4-F 83240-241 (THF-AcOEt) 293 Me F 3-Cl, 4-F 86 230-231 (THF-AcOEt) 294 Me Cl3,4-F₂ 69 248-251 (THF-AcOEt) 295 Me F 3,4-F₂ 71 253-255 (THF-AcOEt) 296Me Cl 3-Br 81 221-222 (THF-AcOEt) 297 Me F 3-Br 80 222-223 (THF-AcOEt)298 Me Cl 4-OCF₃ 76 239-241 (THF-AcOEt) 299 Me F 4-OCF₃ 70 239-240(THF-AcOEt) 300 Me Cl 3-OCF₃ 40 171-175 (THF-AcOEt) 301 Me F 3-OCF₃ 51166-169 (THF-AcOEt) 302 Me Cl 3-NO₂ 80 234-236 (THF-AcOEt) 303 Me F3-NO₂ 80 235-238 (THF-AcOEt) 304 F Cl H 63 199-203 (AcOEt-hexane) 305 FF H 68 204-206 (AcOEt-hexane) 306 F Cl 3-Cl 67 200-201 (AcOEt-hexane)307 F F 3-Cl 77 206-207 (AcOEt-hexane)

Example 308

Synthesis of methyl(2E)-3-[3-[7-chloro-3-(2-[[4-chloro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl)-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]-2-propenoate

A solution of2-[4-(3-bromophenyl)-7-chloro-6-methyl-2-oxo-2H-chromene-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide(500 mg) in DMF (5 ml) was combined with methyl acrylate (0.14 ml),triethylamine (0.21 ml), pd(OAc)₂ (5 ml) and triphenylphosphine (10 mg)under argon atmosphere, and heated at 120° C. for 3 hours. After thereaction was completed, the mixture was combined with water, andextracted with ethyl acetate. The extract was washed with water, driedover magnesium sulfate, and then concentrated. The resultant residue waspurified by a silica gel chromatography (eluent: hexane-ethylacetate=2:1), and then recrystallized from THF-ethyl acetate to obtainthe title compound as a colorless crystal (333 mg, yield: 67%). Meltingpoint: 202-204° C.

Example 309

Synthesis of(2E)-3-[3-[7-chloro-3-(2-[[4-chloro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl)-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]-2-propenoicacid

A solution of ethyl(2E)-3-[3-[7-chloro-3-(2-[[4-chloro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl)-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]-2-propenoate(200 mg) in a mixture of ethanol (5 ml) and THF (2 ml) was combined witha 1 N aqueous solution of sodium hydroxide (3 ml), and stirred at roomtemperature for 4 hours. After 1 N hydrochloric acid (10 ml) was added,the mixture was extracted with ethyl acetate. The extract was washedwith water, dried over magnesium sulfate, and then concentrated. Theresultant crude crystal was recrystallized from THF-ethyl acetate toobtain the title compound as a colorless crystal (137 mg, yield: 70%).Melting point: 191-194° C.

Example 310

Synthesis of2-[4-(3-aminophenyl)-7-chloro-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide

A mixture solution of2-[7-chloro-6-methyl-4-(3-nitrophenyl)-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide(300 mg) in ethanol (2 ml) and THF (5 ml) was combined with Raney-nickel(50 mg), and stirred under hydrogen atmosphere at room temperature for 5hours. After catalyst was filtered off, the reaction solution wasconcentrated. The resultant residue was purified by a silica gelchromatography (eluent: hexane-ethyl acetate=2:1), and furtherrecrystallized from THF-ethyl acetate to obtain the title compound as acolorless crystal (166 mg, yield: 59%). Melting point: 206-207° C.

Example 311-316

The compounds of table 43 were obtained by the method similar to that inExample 1.

TABLE 43

Melting Point (° C.) Example Yield (Recrystallization number R¹ R² (%)solvent) 311 3-Cl 3,5-(CF₃)₂ 72 236-237 (THF-AcOEt) 312 3-Cl 2,5-(CF₃)₂64 242-244 (THF-AcOEt) 313 3,5-(Me)₂ 2-Me, 4-Cl 64 275-276 (THF) 314 Me2,3,5-(Me)₃, 49 150-151 (THF-AcOEt) 4-OH 315 Me 2,3,5-(Me)₃, 70 173-176(THF-AcOEt) 4-OH 316 Me 2,3,5-(Me)₃, 73 248 (decomp.) (THF-IPE) 4-OH

Reference Example 88-93

The compounds of table 44 were obtained by the method similar to that inReference Example 13.

TABLE 44

Ref.Ex. Yield Melting Point (° C.) number R (%) (Recrystallizationsolvent) 88 7-Cl 83 178-181 (AcOEt-IPE) 89 6-OMe, 7-Cl 86 226-229(AcOH-H₂O) 90 6,7-Me₂ 90 213-215 (AcOH) 91 6-Cl, 7-Me 85 218-220 (AcOH)92 6,7-Cl₂ 79 231-233 (AcOH) 93 6,7-F₂ 80 199-201 (AcOH)

Example 317-328

The compounds of table 45 were obtained by the method similar to that inExample 15.

TABLE 45

Example Yield Melting Point (° C.C) number R¹ R² (%) (Recrystallizationsolvent) 317 7-Cl Cl 70 160-164 (AcOEt-hexane) 318 7-Cl F 61 170-175(AcOEt-hexane) 319 6-OMe, Cl 78 209-211 (AcOEt-hexane) 7-Cl 320 6-OMe, F78 202-206 (AcOEt-hexane) 7-Cl 321 6,7-Me₂ Cl 76 206-208 (AcOEt-hexane)322 6,7-Me₂ F 76 200-202 (AcOEt-hexane) 323 6-Cl, Cl 82 222-225(AcOEt-hexane) 7-Me 324 6-Cl, F 85 196-199 (AcOEt-hexane) 7-Me 3256,7-Cl₂ Cl 82 213-215 (AcOEt-hexane) 326 6,7-Cl₂ F 87 222-224(AcOEt-hexane) 327 6,7-F₂ Cl 85 192-194 (AcOEt-hexane) 328 6,7-F₂ F 70176-178 (AcOEt-hexane)

Reference Example 94

(4-Chloro-2-hydroxy-5-methylphenyl)(pyridin-3-yl)methanone

A solution of 3-pyridinecarbaldehyde (2.2 g) in THF (50 ml) was treateddropwise with a solution (50 ml) of Grignard reagent prepared from1-bromo-4-chloro-2-methoxy-5-methylbenzene (5.0 g) and magnesium (0.8 g)in THF at 0° C., and stirred for 1 hour. The reaction solution wascombined with a saturated aqueous solution of ammonium chloride, andextracted with ethyl acetate. The extract was washed with water, driedover magnesium sulfate, and concentrated under reduced pressure. Theresultant residue was used in the next step without purification,combined with toluene (150 ml) and manganese dioxide (15 g), and heatedunder reflux with dehydrating using Deen Stark for 1 hour. After thereaction was completed, the reaction solution was filtered using celite,the filtrate was concentrated under reduced pressure. The resultantresidue was combined with methylene chloride (50 ml) and a 1 N solutionof BBr₃/methylene chloride (60 ml), and stirred at room temperatureovernight. After the reaction was completed, water was added, and thesolvent was distilled off under reduced pressure. The resultant residuewas neutralized with the addition of a saturated aqueous solution ofsodium hydrogen carbonate, and then extracted with ethyl acetate. Theextract was washed with water, and then dried over magnesium sulfate,and concentrated under reduced pressure. The resultant residue waspurified by a silica gel column (eluent: ethyl acetate) to obtain thetitle compound as an oil (2.4 g).

NMR (CDCl₃) δ: 2.28 (3H, s), 7.14 (1H, s), 7.37 (1H, s), 7.50 (1H, dd,J=8 Hz, 4 Hz), 8.00 (1H, m), 8.84 (1H, dd, J=4 Hz, 2H), 8.90 (1H, d, J=2Hz), 11.75 (1H, s).

Reference Example 95

Synthesis of(7-chloro-6-methyl-2-oxo-4-pyridin-3-yl-2H-chromen-3-yl)aceticAcid.Hydrochloride

The title compound (yield: 67%) was obtained by the method similar tothat in Reference Example 13. Melting Point: 279-281° C. (methanol).

Reference Example 96

Synthesis of[4-chloro-2-hydroxy-5-[(4-phenylpiperazin-1-yl)methyl]phenyl](pyridin-3-yl)methanone

The title compound (yield: 63%) was obtained by the method similar tothat in Reference Example 93.

NMR (CDCl₃) δ: 2.65 (4H, t, J=5 Hz), 3.14 (4H, t, J=5 Hz), 3.59 (2H, s),6.80-9.00 (12H, m).

Reference Example 97

Synthesis of ethyl[7-chloro-2-oxo-6-[(4-phenylpiperazin-1-yl)methyl]-4-pyridin-3-yl-2H-chromen-3-yl]acetate

The title compound (yield: 22%) was obtained by the method similar tothat in Reference Example 21. Melting Point: 153-157° C. (ethylacetate-isopropyl ether).

Reference Example 98

Synthesis of ethyl[7-chloro-6-methyl-2-oxo]-4-pyridin-3-yl-2H-chromen-3-yl]acetate(Alternative Synthesis Method of the Compound of Reference Example 21)

(4-Chloro-2-hydroxy-5-methylphenyl)(phenyl)methanone (130 g) wassuspended in acetonitrile (325 ml), and combined with DBU (217 g) atroom temperature. The mixture was heated to approximately 40° C., andtreated dropwise with a solution of ethylsuccinyl chloride (147 g) inacetonitrile (234 ml) with keeping the reaction temperature at 40 to 45°C. After completing dropwise addition, the mixture was stirred at 40 to45° C. for 30 minutes. The mixture was combined with water, stirred at40° C. for 30 minutes, cooled to room temperature, and further stirredat 0 to 5° C. internal temperature with cooling in ice for 1 hour. Thecrystal precipitated was filtered, and washed with cooled CH₃CN—H₂O=3:2to obtain the title compound as a slightly tan white crystal (140 g,yield: 74%).

NMR (CDCl₃) δ: 1.23 (3H, t, J=7 Hz), 2.28 (2H, s), 3.36 (2H, s), 4.13(2H, t, J=7 Hz), 6.84 (1H, s), 7.20-7.35 (2H, m), 7.41 (1H, s),7.45-7.60 (3H, m).

Example 329-330

The compounds of table 46 were obtained by the method similar to that inExample 15.

TABLE 46

Example Yield Melting Point (° C.) number R (%) (Recrystallizationsolvent) 329 Cl 64 212-215 (THF-AcOEt) 330 F 53 213-215 (THF-AcOEt)

Example 331

Synthesis of2-[7-chloro-2-oxo-4-phenyl-6-[(4-phenyl-1-piperazinyl)methyl]-2H-chromen-3-yl]-N-(4-hydroxy-2,3,5-trimethylphenyl)acetamide

A solution of2-[7-chloro-2-oxo-4-phenyl-6-[(4-phenyl-1-piperazinyl)methyl]-2H-chromen-3-yl]-N-(4-hydroxy-2,3,5-trimethylphenyl)aceticacid (200 mg) in DMF (2 ml) was combined with4-amino-2,3,6-trimethylphenol (68 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (118 mg) and1-hydroxybenzotriazole (83 mg), and stirred at room temperatureovernight. The reaction solution was combined with water, and theprecipitate formed was filtered. The resultant crude crystal waspurified by a silica gel chromatography (eluent: hexane-ethylacetate=1:1), and further recrystallized from ethyl acetate to obtainthe title compound as a colorless crystal (84 mg, yield: 33%). Meltingpoint: 193° C. (decomp.).

Example 332-333

The compounds of table 47 were obtained by the method similar to that inExample 331.

TABLE 47

Melting Point (° C.) Example Yield (Recrystallization number R (%)solvent) 332 2-Me, 4-Cl 20 290-292 (AcOEt-IPE) 333 2,3,5-(Me)₃, 4-OH 36242-246 (AcOEt-IPE)

Example 334

Synthesis of2-[7-chloro-2-oxo-6-[(4-phenyl-1-piperazinyl)methyl]-4-(3-pyridinyl)-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide

A suspension of ethyl7-chloro-2-oxo-6-[(4-phenyl-1-piperazinyl)methyl]-4-(3-pyridinyl)-2H-chromen-3-yl]acetate(500 mg, 0.97 mmol) in ethanol (10 ml) was combined with a 2 N aqueoussolution of sodium hydroxide (1.5 ml), and heated and stirred at 70° C.for 1 hour. After allowing to cool, the mixture was combined with 1 Nhydrochloric acid (3 ml), and neutralized with a saturated aqueoussolution of sodium hydrogen carbonate. The solvent was distilled offunder reduced pressure, and the residue was boiled azeotropically withtoluene to remove water. The resultant yellow powder (350 mg) wascombined with THF (5 ml), DMF (1 drop) and thionyl chloride (0.22 ml),and stirred at room temperature for 2 hours. The solvent was distilledoff under reduced pressure, and the residue was combined with THF (15ml) and 2-amino-5-chlorobenzotrifluoride (0.38 ml, 2.1 mmol), andstirred at 80° C. for 15 hours. After allowing to cool, the mixture wascombined with an aqueous solution of ammonium chloride, and extractedwith ethyl acetate. The extract was washed with a saturated aqueoussolution of sodium chloride, and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. The resultantresidue was purified by a silica gel column chromatography (eluent:hexane-ethyl acetate=1:1), and further recrystallized from ethylacetate-isopropyl ether to obtain the title compound as a colorlesscrystal (102 mg, yield: 21%). Melting point: 214-216° C.

Example 335

Synthesis of2-[7-chloro-2-oxo-6-[(4-phenyl-1-piperazinyl)methyl]-4-(3-pyridinyl)-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide

The title compound (yield: 21%) obtained by the method similar to thatin Example 334. Melting point: 202-205° C. (ethyl acetate-isopropylether).

Example 336-337

The compounds of table 48 were obtained by the method similar to that inExample 308.

TABLE 48

Example Yield Melting Point (° C.) number R (%) (Recrystallizationsolvent) 336 Cl 64 118 (decomp.) (AcOEt) 337 F 39 193-196 (AcOEt)

Example 338

Synthesis of ethyl3-[3-[7-chloro-3-(2-[[4-chloro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl)-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]-2-propionate

A mixture solution of ethyl(2E)-3-[3-[7-chloro-3-(2-[[4-chloro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl)-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]-2-propenate(138 mg) in ethanol (5 ml) and THF (2 ml) was combined with Raney-nickel(approximately 100 mg), stirred under hydrogen atmosphere at roomtemperature for 4 hours. After the catalyst was filtered off usingcelite, the filtrate was concentrated. The resultant residue waspurified by a silica gel chromatography (eluent: hexane-ethylacetate=2:1), and recrystallized from ethyl acetate to obtain the titlecompound as a colorless crystal (131 mg, yield: 95%). Melting point:116° C. (decomp.).

Example 339 to 340

The compounds of table 49 were obtained by the method similar to that inExample 309.

TABLE 49

Example Yield Melting Point (° C.) number R X (%) (Recrystallizationsolvent) 339 F CH═CH 80 260-262 (AcOEt) 340 Cl CH₂—CH₂ 89 170-172(AcOEt)

In the Formulation Examples and Experiments described below, CompoundsA, B and C are those shown below, respectively.

Compound A:2-[6-chloro-2-oxo-4-(2-methylphenyl)-2H-chromen-3-yl]-N-(2,6-dimethoxyphenyl)acetamide;

Compound B:N-(2,6-dimethoxyphenyl)-N′-[3-(2-methylphenyl)-6,7-dihydro-5H-indeno[5,6-b]furan-2-yl]urea;

Compound C:N-(4-chloro-2-trifluoromethylphenyl)-2-(2-oxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetamide.

Formulation Examples

A lipid-rich plaque regressing agent containing as an active ingredienta compound [I], [II], [III], [IV], [V] or [VI] or its salt of thepresent invention can be produced for example in the followingformulations.

1. Capsule

(1) Compound A 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70mg (4) Magnesium stearate 10 mg 1 Capsule 180 mg

(1), (2) and (3) and ½ of (4) are mixed and granulated. To this, theremainder of (4) is added and the entire is encapsulated into a gelatincapsule.

2. Tablet

(1) Compound A 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4)Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 Tablet230 mg

(1), (2), (3), ⅔ of (4) and ½ of (5) are mixed and granulated. To thisgranule, the remainder of (4) and (5) are added and compressed into atablet.

3. Injection Formulation

(1) Compound A 10 mg (2) Inositol 100 mg (3) Benzyl alcohol 20 mg 1Ampoule 130 mg

(1), (2) and (3) are dissolved in distlled water for injection to makethe total volume 2 ml, and charged in an ampoule. All processes areconducted aseptically.

4. Capsule

(1) Compound B 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70mg (4) Magnesium stearate 10 mg 1 Capsule 180 mg

(1), (2) and (3) and ½ of (4) are mixed and granulated. To this, theremainder of (4) is added and the entire is encapsulated into a gelatincapsule.

5. Tablet

(1) Compound B 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4)Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 Tablet230 mg

(1), (2), (3), ⅔ of (4) and ½ of (5) are mixed and granulated. To thisgranule, the remainder of (4) and (5) are added and compressed into atablet.

6. Injection Formulation

(1) Compound B 10 mg (2) Inositol 100 mg (3) Benzyl alcohol 20 mg 1Ampoule 130 mg

(1), (2) and (3) are dissolved in distlled water for injection to makethe total volume 2 ml, and charged in an ampoule. All processes areconducted aseptically.

7. Capsule

(1) Compound C 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70mg (4) Magnesium stearate 10 mg 1 Capsule 180 mg

(1), (2) and (3) and ½ of (4) are mixed and granulated. To this, theremainder of (4) is added and the entire is encapsulated into a gelatincapsule.

8. Tablet

(1) Compound C 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4)Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 Tablet230 mg

(1), (2), (3), ⅔ of (4) and ½ of (5) are mixed and granulated. To thisgranule, the remainder of (4) and (5) are added and compressed into atablet.

9. Injection Formulation

(1) Compound C 10 mg (2) Inositol 100 mg (3) Benzyl alcohol 20 mg 1Ampoule 130 mg

(1), (2) and (3) are dissolved in distlled water for injection to makethe total volume 2 ml, and charged in an ampoule. All processes areconducted aseptically.

10. Capsule

(1) Compound C 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70mg (4) Magnesium stearate 10 mg 1 Capsule 180 mg

(1), (2) and (3) and ½ of (4) are mixed and granulated. To this, theremainder of (4) is added and the entire is encapsulated into a gelatincapsule.

11. Tablet

(1) Compound C 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg  (4)Microcrystalline cellulose 30 mg (5) Magnesium stearate  5 mg 1 Tablet230 mg 

(1), (2), (3), ⅔ of (4) and ½ of (5) are mixed and granulated. To thisgranule, the remainder of (4) and (5) are added and compressed into atablet.

12. Capsule

(1) Compound C 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70mg (4) Magnesium stearate 10 mg 1 Capsule 180 mg 

(1), (2) and (3) and ½ of (4) are mixed and granulated. To this, theremainder of (4) is added and the entire is encapsulated into a gelatincapsule.

13. Tablet

(1) Compound B 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg  (4)Microcrystalline cellulose 30 mg (5) Magnesium stearate  5 mg 1 Tablet230 mg 

(1), (2), (3), ⅔ of (4) and ½ of (5) are mixed and granulated. To thisgranule, the remainder of (4) and (5) are added and compressed into atablet.

14. Capsule

(1) Compound B 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70mg (4) Magnesium stearate 10 mg 1 Capsule 180 mg 

(1), (2) and (3) and ½ of (4) are mixed and granulated. To this, theremainder of (4) is added and the entire is encapsulated into a gelatincapsule.

15. Tablet

(1) Compound A 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg  (4)Microcrystalline cellulose 30 mg (5) Magnesium stearate  5 mg 1 Tablet230 mg 

(1), (2), (3), ⅔ of (4) and ½ of (5) are mixed and granulated. To thisgranule, the remainder of (4) and (5) are added and compressed into atablet.

16. Tablet

According to the formulation indicated below, a mixture of 175 g ofCompound C, 175 g of D-mannitol, 118.65 g of corn starch and 105 g ofcroscarmellose sodium is mixed thoroughly using a vertical granulator(Model FM-VG-10, Powrex), and then kneaded with an aqueous solution inwhich 19.25 g of hydroxypropyl cellulose is dissolved (kneadingcondition: 400 rpm, 10 minutes). After drying the kneaded white materialin a fluidized drier (FD-3S, Powrex) at the blowing temperature of 60°C. for 30 minutes, the material is sieved through a 1.5 mmφ punchingscreen using a power mill (model P-3S, SHOWAKAGAKU KIKAI KOSAKUSHO).525.14 g of this granule, 31 g of croscarmellose sodium and 1.86 g ofmagnesium stearate are added, and mixed in a mixer (model TM-15,SHOWAKAGAKU KIKAI KOSAKUSHO) for 5 minutes to obtain a granule fortablet compaction. This granule is compressed in 180 mg aliquots by atabletting machine (Correct 19K, KIKUSUI SEISAKUSHO) using a 8.0 mmφedged plain mallet under 0.7 ton/cm2, whereby obtaining 2,350 tablets.

Compound C 50 mg D-Mannitol 50 mg Corn starch 33.9 mg Croscarmellosesodium 40 mg Hydroxypropyl cellulose 5.5 mg Magnesium stearate 0.6 mgTotal 180.0 mg (per tablet)17. Solid Dispersion A

Compound of Example 75 0.4 g Hydroxypropylmethyl cellulose phthalate 1.4g Lactose 0.2 g Total 2.0 g

The compound of Example 75 (0.4 g) was dissolved in methylene chloride(24 ml) and ethanol (16 ml), to which hydroxypropylmethyl cellulosephthalate (HP-50, SHINETSUKAGAKU, 1.4 g) was added and dissolved. Tothis solution, lactose (0.2 g) was added and suspended uniformly, andthen the organic solvent was distilled off using a spray drier (YAMATOKAGAKU). The product was dried under reduced pressure using a vacuumdrier for 14 hours to obtain a solid dispersion (1.4 g) of the compoundof Example 75.

18. Solid Dispersion B

Compound of Example 75 0.6 g Hydroxypropylmethyl cellulose phthalate 1.2g Lactose 0.2 g Total 2.0 g

The compound of Example 75 (0.6 g) was dissolved in methylene chloride(24 ml) and ethanol (16 ml), to which hydroxypropylmethyl cellulosephthalate (HP-50, SHINETSUKAGAKU, 1.2 g) was added and dissolved. Tothis solution, lactose (0.2 g) was added and suspended uniformly, andthen the organic solvent was distilled off using a spray drier (YAMATOKAGAKU). The product was dried under reduced pressure using a vacuumdrier for 14 hours to obtain a solid dispersion (1.4 g) of the compoundof Example 75.

19. Tablet

(1) Solid dispersion A 50 mg (2) Lactose 34 mg (3) Corn starch 10.6 mg(4) Corn starch (gelatinized) 5 mg (5) Magnesium stearate 0.4 mg (6)Calcium carboxymethyl cellulose 20 mg Total 120 mg

According to an ordinary method, (1) to (6) were mixed and compressedinto a tablet using a tabletting machine. Using Solid dispersion Binstead of Solid dispersion A, a tablet was also obtained.

Experiments

The lipid-rich plaque regressing effect of a compound [I], [II], [III],[IV], [V] or [VI] or its salt of the present invention is discussedbelow with referring to Experiments.

Experiment 1

[Method] A 5-week old male apo-lipoprotein E deficient mouse whichexhibits a vascular lesion similar to a human arteriosclerotic lesion(hereinafter referred to as male apoE mouse) was maintained with anarteriosclerotic diet which was a CE-2 diet (normal diet, NIPPON CLEA)supplemented with 1.25% cholesterol for 8 weeks. Subsequently, each ofonly CE-2 powder, which is a normal diet, (control group, number ofanimals=8) and CE-2 powder supplemented with Compound A (number ofanimals=8) was given ad libitum during the period from the 9th week tothe 12th week. Each animal was sacrificed by decapitation 12 weeks afterinitiation of the experiment, the vessel from the aortic arch to thefemoral bifurcation was isolated and opened in the direction of thevascular axis, stained with oil red O (Sigma Aldrich Japan),photographed closely using a medical Nikkor (NIKON), and the photographwas scanned using a scanner (GT-6000, EPSON) and the image was processedusing Adobe Photoshop. Thus, the image of the vessel was trimmed and thered color was extracted and modified into a two-tone gradation.

The two-tone image was subjected to an NIH image (National Institute ofHealth) to count pixels, whereby calculating the % lesion area based onthe entire surface area of the internal wall of the vessel.

[Results] The lesion (plaque) area based on the vascular internalsurface area was 31% in the group fed only the normal diet after 9thweek. On the contrary, the administraiton of Compound A mixed with thenormal diet at the dose of 27 mg/kg/day resulted in a marked reductionin the vascular lesion area to 15%, showing a significant (p<0.01,student's test) plaque regressing effect.Experiment 2[Method] A 6-week old male apo-lipoprotein E deficient mouse exhibitinga vascular lesion similar to a human arteriosclerotic lesion(hereinafter referred to as male apoE KO mouse) was maintained with anarteriosclerotic diet which was a CE-2 diet (normal diet, NIPPON CLEA)supplemented with 1.25% cholesterol for 8 weeks. Subsequently, from the9th week to the 12th week, Compound B (0.5% methyl cellulose suspension:at 30 mg/kg/day) was administered orally, during the period only CE-2powder, which is a normal diet, was given. The control group wasmaintained with only CE-2 diet. Each animal was sacrificed bydecapitation 12 weeks after initiation of the experiment, the vesselfrom the aortic arch to the femoral bifurcation was isolated and openedin the direction of the vascular axis, stained with oil red O (SigmaAldrich Japan), and subjected to an image analysis similarly toExperiment 1 to calculate the % lesion area based on the entire vascularinternal wall area. The vessel specimen after the image analysis washomogenized in saline, and the amount of cholesteryl ester content inthe aorta was measured in accordance with the method by Hara and Radin(Lipid Extract of tissues with a low-Toxicity solvent, Anal. Biochem.,90:420-426, 1978), that is, from the aorta stained with the oil red Owas extracted the lipid by a glass homogenizer with hexane:isopropylalcohol (3:2) and centrifuged. Subsequently, the supernatant wasrecovered and evaporated to dryness, and then dissolved in TESIT:dioxane (1:1). From this solution, its total cholesterol content(Cholesterol C test, WAKO) and the free cholesterol content (FreeCholesterol C test, WAKO) were examined. The data obtained werecorrected for the wet weight of the aorta. The cholesteryl ester content(CE) was obtained by subtracting the free cholesterol content from thetotal cholesterol content. Since the sample, which was extracted withhexane:isopropyl alcohol and then evaporated to dryness, contained theoil red O which interferes with the absorption wavelength for thecholesterol measurement, the cholesterol content was calculated for eachsample by subtracting the blank level (absorbance of oil red O insample).[Results] The results are shown in Table 50.

TABLE 50 Control group Compound B group (n = 8) (n = 4) % Lesion area22.6 ± 3.0 16.9 ± 1.6 Aortic cholesteryl 9.42 ± 0.66 4.76 ± 0.46** Estercontent (μg/mg) n: Number of animals, **: P < 0.05% (Dunnett's test)

After maintaining apoE KO mice with the arteriosclerotic diet for 8weeks followed by the normal diet for 4 weeks, the % lesion area was22.6% and the aortic cholesteryl ester content was 9.42 μg/ml (controlgroup). On the other hand, the arteriosclerotic diet for 8 weeksfollowed by the normal diet with 30 mg/kg/day of Compound B given byoral administraiton for 4 weeks resulted in the marked reduction of thelesion area to 16.9% and the aortic cholesteryl ester content to 4.76μg/ml, which shows a plaque regressing effect.

Experiment 3

[Method] A 6-week old male apo-lipbprotein E deficient mouse exhibitinga vascular lesion similar to a human arteriosclerotic lesion(hereinafter referred to as male apoE KO mouse) was maintained with anarteriosclerotic diet which was a CE-2 diet (normal diet, NIPPON CLEA)supplemented with 1.25% cholesterol for 8 weeks. Subsequently, duringthe period from the 9th week to the 12th week, and Compound C (0.5%methyl cellulose suspension: at 10 mg/kg/day) was administered orallyonly, during the period only CE-2 powder, which is a normal diet, wasgiven. The control group was maintained with only CE-2 diet. Each animalwas sacrificed by decapitation 12 weeks after initiation of theexperiment, the vessel from the aortic arch to the femoral bifurcationwas isolated and opened in the direction of the vascular axis, stainedwith oil red O (Sigma Aldrich Japan), and subjected to an image analysissimilarly to Experiment 1 to calculate the % lesion area based on theentire vascular internal wall area. The vessel specimen after the imageanalysis was homogenized in saline, and the amount of cholesteryl estercontent in the aorta was measured by an enzymatic method similarly toExperiment 2 described above.[Results] The results are shown in Table 51.

TABLE 51 Control group Compound B group (n = 10) (n = 10) % Lesion area31.2 ± 1.6  23.3 ± 1.8* Aortic cholesteryl 6.83 ± 0.42 5.30 ± 0.37 Estercontent (μg/mg) n: Number of animals *P < 0.05% (Dunnett's test)

After maintaining apoE KO mice with the arteriosclerotic diet for 8weeks followed by the normal diet for 4 weeks, the % lesion area was31.2% and the aortic cholesteryl ester content was 6.83 μg/ml (controlgroup). On the other hand, the arteriosclerotic diet for 8 weeksfollowed by the normal diet with 30 mg/kg/day of Compound C given byoral administraiton for 4 weeks resulted in the marked reduction of thelesion area to 23.3% and the aortic cholesteryl ester content to 5.30μg/ml, which shows a plaque regressing effect.

INDUSTRIAL APPLICABILITY

Since the lipid-rich plaque regressing agent containing the compound[I], [II], [III], [IV], [V] or [VI], or their salts, or the prodrugthereof, of the present invention exhibits an excellent lipid-richplaque regressing effect, they are useful in preventing and treatingacute coronary artery syndrome such as acute myocardial infarction andunstable angina, peripheral artery occlusion and the like.

1. A compound selected from the group consisting of:(2E)-3-[3-[7-chloro-3-(2-[[4-chloro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl)-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]propenoicacid;(2E)-3-[3-[7-chloro-3-(2-[4-fluoro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl)-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]propenoicacid; and3-[3-[7-chloro-3-(2-[[4-chloro-2-(trifluorornethyl)phenyl]amino]-2-oxoethyl)-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]propanoicacid, or a salt thereof.
 2. A pharmaceutical composition comprising acompound according to claim 1 or a salt thereof, and a pharmaceuticallyacceptable carrier, excipient or diluent.
 3. A method for regressing alipid-rich plaque in a mammal in need thereof, comprising administeringan effective amount of a compound according to claim 1 or a salt.
 4. Amethod for treating acute coronary artery syndrome in a mammal in needthereof, comprising administering an effective amount of a compound ofclaim 1 or a salt thereof, to said mammal.
 5. A method for treatingacute myocardial infarction in a mammal in need thereof, comprisingadministering an effective amount of a compound of claim 1 or a saltthereof, to said mammal.
 6. A method for treating unstable angina in amammal in need thereof, comprising administering an effective amount ofa compound of claim 1 or a salt thereof, to said mammal.
 7. A method fortreating peripheral artery occlusion in a mammal in need thereof,comprising administering an effective amount of a compound of claim 1 ora salt thereof, to said mammal.